|
1
|
Moustafa YM, Mageed SSA, El-Dakroury WA, Moustafa HAM, Sallam AAM, Abulsoud AI, Abdelmaksoud NM, Mohammed OA, Nomier Y, Elesawy AE, Abdel-Reheim MA, Zaki MB, Rizk NI, Ayed A, Ibrahim RA, Doghish AS. Exploring the molecular pathways of miRNAs in testicular cancer: from diagnosis to therapeutic innovations. Funct Integr Genomics 2025; 25:88. [PMID: 40229500 DOI: 10.1007/s10142-025-01599-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/16/2025]
Abstract
Cancer diagnostics highlight the critical requirement for sensitive and accurate tools with functional biomarkers for early tumor detection, diagnosis, and treatment. With a high burden of morbidity and mortality among young men worldwide and an increasing prevalence, Testicular cancer (TC) is a significant death-related cancer. Along with patient history, imaging, clinical presentation, and laboratory data, histological analysis of the testicular tissue following orchiectomy is crucial. Although some patients in advanced stages who belong to a poor risk group die from cancer, surgical treatments and chemotherapeutic treatment offer a high possibility of cure in the early stages. Testicular tumors lack useful indicators despite their traditional pathological classification, which highlights the need to find and use blood tumor markers in therapy. Regretfully, the sensitivity and specificity of the currently available biomarkers are restricted. Novel non-coding RNA molecules, microRNAs (miRNAs), have recently been discovered, offering a potential breakthrough as viable biomarkers and diagnostic tools. They act as fundamental gene regulators at the post-transcriptional level, controlling cell proliferation, differentiation, and apoptosis. This article aims to comprehensively explore the role of miRNAs in the pathophysiology, diagnosis, and treatment of TC, with a focus on their regulatory mechanisms within key signaling pathways such as TGF-β, PTEN/AKT/mTOR, EGFR, JAK/STAT, and WNT/β-catenin. By investigating the potential of miRNAs as diagnostic and prognostic biomarkers and therapeutic targets, this study seeks to address challenges such as treatment resistance and evaluate the clinical importance of miRNAs in improving patient outcomes. Additionally, the work aims to explore innovative approaches, including nanoparticle-based delivery systems, to enhance the efficacy of miRNA-based therapies. Ultimately, this research aims to provide insights into future directions for precision medicine in TC, bridging the gap between molecular discoveries and clinical applications.
Collapse
Affiliation(s)
- Yasser M Moustafa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Hebatallah Ahmed Mohamed Moustafa
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, 11566, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | - Yousra Nomier
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | | | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Menoufia, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Menoufia National University, Km Cairo-Alexandria Agricultural Road, Menofia, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt
| | - Abdullah Ayed
- Department of Surgery, College of Medicine, University of Bisha, P.O Box 551, 61922, Bisha, Saudi Arabia
| | - Randa A Ibrahim
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
| |
Collapse
|
|
2
|
Zhan Z, Luo X, Shi J, Chen L, Ye M, Jin X. Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors and potential therapeutic agents (Review). Exp Ther Med 2025; 29:82. [PMID: 40084198 PMCID: PMC11904865 DOI: 10.3892/etm.2025.12832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/31/2024] [Indexed: 03/16/2025] Open
Abstract
Testicular germ cell tumors (TGCTs) are the most common tumors in men aged 20-40 years and are primarily treated with cisplatin-based drugs. Although TGCTs are highly sensitive to DNA damage induced by cisplatin and show a hypersensitive apoptotic response, cisplatin resistance still exists. Emerging evidence shows that cisplatin resistance in TGCTs is mainly related to the inhibition of apoptotic pathways such as MDM2/p53, OCT4/NOXA, PDGFR/PI3K/AKT, inhibition of cell cycle checkpoints, increased methylation or neddylation and DNA repair balance. In this review, recent advances regarding the mechanisms of TGCTs' sensitivity and resistance to cisplatin were summarized and potential therapeutic agents for cisplatin-resistant TGCTs were presented, providing a new therapeutic strategy for drug-resistant TGCTs.
Collapse
Affiliation(s)
- Ziqing Zhan
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Tumor Chemoradiotherapy, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Xia Luo
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Tumor Chemoradiotherapy, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Jiaxin Shi
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Tumor Chemoradiotherapy, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Litao Chen
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Tumor Chemoradiotherapy, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Meng Ye
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Tumor Chemoradiotherapy, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Tumor Chemoradiotherapy, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| |
Collapse
|
|
3
|
Doghish AS, Elsakka EGE, Moustafa HAM, Ashraf A, Mageed SSA, Mohammed OA, Abdel-Reheim MA, Zaki MB, Elimam H, Rizk NI, Omran SA, Farag SA, Youssef DG, Abulsoud AI. Harnessing the power of miRNAs for precision diagnosis and treatment of male infertility. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3271-3296. [PMID: 39535597 DOI: 10.1007/s00210-024-03594-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Infertility is a multifactorial reproductive system disorder, and most infertility cases occur in men. Semen testing is now thought to be the most important diagnostic test for infertile men; nonetheless, because of its limitations, the cause of infertility remains unknown for 40% of infertile men. Semen assessment's shortcomings indicate the need for improved and innovative diagnostic techniques and biomarkers worldwide. Non-coding RNAs with a length of roughly 18-22 nucleotides are called microRNAs (miRNAs). Most of our protein-coding genes are post-transcriptionally regulated by them. These molecules are unusual in bodily fluids, and aberrant variations in their expression can point to specific conditions like infertility. As a result, fresh potential biomarkers for the diagnosis and prognosis of various forms of male infertility may be represented by miRNAs. This review examined the most recent research revealing the association between different miRNAs' functions in male infertility and their expression patterns. Also, it aims to figure out the most recent strategies that could be applied for using such miRNAs as possible therapeutic targets for infertility treatment.
Collapse
Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City , 11829, Cairo, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Hebatallah Ahmed Mohamed Moustafa
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Alaa Ashraf
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | | | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Menoufia, Egypt
| | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Menoufia, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Nasr City, 11786, Egypt, Cairo
| | - Sarah A Omran
- Pharmacognosy Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Shimaa A Farag
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Donia G Youssef
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, El-Salam City, Cairo, 11785, Egypt
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| |
Collapse
|
|
4
|
Li Z, Wu YH, Guo YQ, Min XJ, Lin Y. Tasquinimod promotes the sensitivity of ovarian cancer cells to cisplatin by down-regulating the HDAC4/p21 pathway. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2025; 29:191-204. [PMID: 39539173 PMCID: PMC11842298 DOI: 10.4196/kjpp.24.132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/03/2024] [Accepted: 08/06/2024] [Indexed: 11/16/2024]
Abstract
To investigate whether Tasquinimod can influence cisplatin resistance in drug-resistant ovarian cancer (OC) cell lines by regulating histone deacetylase 4 (HDAC4) or p21, we explored its effects on the cell cycle, and associated mechanisms. RT-PCR and Western blot analyses, flow cytometry, CCK8 assay, and immunofluorescence were utilized to investigate the effects of Tasquinimod on gene expression, cell cycle, apoptosis, viability, and protein levels in OC cells. The results showed that Tasquinimod inhibited cell viability and promoted apoptosis in SKOV3/DDP (cisplatin) and A2780/DDP cells more effectively than DDP alone. In combination with cisplatin, Tasquinimod further enhanced cell apoptosis and reduced cell viability in these cell lines, an effect that could be reversed following HDAC4 overexpression. Tasquinimod treatment down-regulated HDAC4, Bcl-2, and cyclin D1, and CDK4 expression and up-regulated the cleaved-Caspase-3, and p21 expression in SKOV3/DDP and A2780/ DDP cells. Additionally, Tasquinimod inhibited DDP resistance in OC/DDP cells. These effects were similarly observed in OC mouse models treated with Tasquinimod. In conclusion, Tasquinimod can improve OC cells' sensitivity to DDP by down-regulating the HDAC4/p21 axis, offering insights into potential strategies for overcoming cisplatin resistance in OC.
Collapse
Affiliation(s)
- Zhao Li
- Department of Gynecology, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410000, Hunan, China
| | - Ya-Hong Wu
- Department of Gynecology, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410000, Hunan, China
| | - Ye-Qing Guo
- Department of Gynecology, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410000, Hunan, China
| | - Xiao-Jia Min
- Department of Gynecology, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410000, Hunan, China
| | - Ying Lin
- Department of Gynecology, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410000, Hunan, China
| |
Collapse
|
|
5
|
Liu X, Hu X, Jing M, Huang L, You Y, Zhang Y, Li K, Tu Y, Liu Y, Chen X, Su J, Hejtmancik JF, Hou L, Ma X. Death associated protein like 1 acts as a novel tumor suppressor in melanoma by increasing the stability of P21 protein. Mol Cell Biochem 2025; 480:1595-1610. [PMID: 38980592 PMCID: PMC11842415 DOI: 10.1007/s11010-024-05067-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 06/30/2024] [Indexed: 07/10/2024]
Abstract
Melanoma is a primary malignant tumor with high lethality, which occurs in the skin and eye tissues, while the molecular mechanisms of melanomagenesis remain largely unknown. Here, we show that death-associated protein-like 1 (DAPL1) expression is lower in melanoma tissues than in paracancerous tissues or nevus tissues, and Uveal melanoma patients with lower DAPL1 expression have a poorer survival rate than those with higher expression of DAPL1. Overexpression of DAPL1 inhibits proliferation of cultured melanoma cells, whereas knockdown of DAPL1 increases cell proliferation. Tumor transplantation experiment results also demonstrate that DAPL1 inhibits tumorigenesis of melanoma cells both in subretinal and subcutaneous tissues of nude mice in vivo. Finally, DAPL1 inhibits proliferation of melanoma cells by increasing the protein level of P21 via decreasing the ubiquitin mediated degradation of P21 and promoting its stability. Conversely, knockdown of P21 neutralizes the effects of inhibition of DAPL1 on melanoma cell proliferation and enhances the severity of melanoma tumorigenesis. These results suggest that DAPL1 is a novel melanoma tumor suppressor gene and thus a potential therapeutic target for melanoma.
Collapse
Affiliation(s)
- Xiaoyan Liu
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaojuan Hu
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Meiyu Jing
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Lijin Huang
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yaqi You
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yaru Zhang
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Ke Li
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yunhai Tu
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Youjia Liu
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaogang Chen
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Jianzhong Su
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - J Fielding Hejtmancik
- Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ling Hou
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaoyin Ma
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
| |
Collapse
|
|
6
|
White-Gilbertson S, Lu P, Saatci O, Sahin O, Delaney JR, Ogretmen B, Voelkel-Johnson C. Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization. J Biol Chem 2024; 300:107136. [PMID: 38447798 PMCID: PMC10979113 DOI: 10.1016/j.jbc.2024.107136] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 02/03/2024] [Accepted: 02/15/2024] [Indexed: 03/08/2024] Open
Abstract
Polyploid giant cancer cells (PGCC) are frequently detected in tumors and are increasingly recognized for their roles in chromosomal instability and associated genome evolution that leads to cancer recurrence. We previously reported that therapy stress promotes polyploidy, and that acid ceramidase plays a role in depolyploidization. In this study, we used an RNA-seq approach to gain a better understanding of the underlying transcriptomic changes that occur as cancer cells progress through polyploidization and depolyploidization. Our results revealed gene signatures that are associated with disease-free and/or overall survival in several cancers and identified the cell cycle inhibitor CDKN1A/p21 as the major hub in PGCC and early progeny. Increased expression of p21 in PGCC was limited to the cytoplasm. We previously demonstrated that the sphingolipid enzyme acid ceramidase is dispensable for polyploidization upon therapy stress but plays a crucial role in depolyploidization. The current study demonstrates that treatment of cells with ceramide is not sufficient for p53-independent induction of p21 and that knockdown of acid ceramidase, which hydrolyzes ceramide, does not interfere with upregulation of p21. In contrast, blocking the expression of p21 with UC2288 prevented the induction of acid ceramidase and inhibited both the formation of PGCC from parental cells as well as the generation of progeny from PGCC. Taken together, our data suggest that p21 functions upstream of acid ceramidase and plays an important role in polyploidization and depolyploidization.
Collapse
Affiliation(s)
- Shai White-Gilbertson
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ping Lu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ozge Saatci
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ozgur Sahin
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Joe R Delaney
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Christina Voelkel-Johnson
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
| |
Collapse
|
|
7
|
Cimadamore A, Franzese C, Di Loreto C, Blanca A, Lopez-Beltran A, Crestani A, Giannarini G, Tan PH, Carneiro BA, El-Deiry WS, Montironi R, Cheng L. Predictive and prognostic biomarkers in urological tumours. Pathology 2024; 56:228-238. [PMID: 38199927 DOI: 10.1016/j.pathol.2023.10.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/29/2023] [Accepted: 10/09/2023] [Indexed: 01/12/2024]
Abstract
Advancements in cutting-edge molecular profiling techniques, such as next-generation sequencing and bioinformatic analytic tools, have allowed researchers to examine tumour biology in detail and stratify patients based on factors linked with clinical outcome and response to therapy. This manuscript highlights the most relevant prognostic and predictive biomarkers in kidney, bladder, prostate and testicular cancers with recognised impact in clinical practice. In bladder and prostate cancer, new genetic acquisitions concerning the biology of tumours have modified the therapeutic scenario and led to the approval of target directed therapies, increasing the quality of patient care. Thus, it has become of paramount importance to choose adequate molecular tests, i.e., FGFR screening for urothelial cancer and BRCA1-2 alterations for prostate cancer, to guide the treatment plan for patients. While no tissue or blood-based biomarkers are currently used in routine clinical practice for renal cell carcinoma and testicular cancers, the field is quickly expanding. In kidney tumours, gene expression signatures might be the key to identify patients who will respond better to immunotherapy or anti-angiogenic drugs. In testicular germ cell tumours, the use of microRNA has outperformed conventional serum biomarkers in the diagnosis of primary tumours, prediction of chemoresistance, follow-up monitoring, and relapse prediction.
Collapse
Affiliation(s)
- Alessia Cimadamore
- Institute of Pathological Anatomy, Department of Medicine (DAME), Udine University, Udine, Italy.
| | - Carmine Franzese
- Department of Urology, Ospedale Santa Maria Della Misericordia di Udine, Udine, Italy
| | - Carla Di Loreto
- Institute of Pathological Anatomy, Department of Medicine (DAME), Udine University, Udine, Italy
| | - Ana Blanca
- Maimonides Biomedical Research Institute of Cordoba, Department of Urology, University Hospital of Reina Sofia, UCO, Cordoba, Spain
| | | | - Alessandro Crestani
- Department of Urology, Ospedale Santa Maria Della Misericordia di Udine, Udine, Italy
| | - Gianluca Giannarini
- Department of Urology, Ospedale Santa Maria Della Misericordia di Udine, Udine, Italy
| | | | - Benedito A Carneiro
- The Legorreta Cancer Center at Brown University, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Lifespan Academic Medical Center, Providence, RI, USA
| | - Wafik S El-Deiry
- The Legorreta Cancer Center at Brown University, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Lifespan Academic Medical Center, Providence, RI, USA
| | - Rodolfo Montironi
- Molecular Medicine and Cell Therapy Foundation, Department of Clinical and Molecular Sciences, Polytechnic University of the Marche Region, Ancona, Italy
| | - Liang Cheng
- The Legorreta Cancer Center at Brown University, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Lifespan Academic Medical Center, Providence, RI, USA.
| |
Collapse
|
|
8
|
Gonzalez T, Muminovic M, Nano O, Vulfovich M. Folate Receptor Alpha-A Novel Approach to Cancer Therapy. Int J Mol Sci 2024; 25:1046. [PMID: 38256120 PMCID: PMC11154542 DOI: 10.3390/ijms25021046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 01/11/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
Folate receptor α (FR) was discovered many decades ago, along with drugs that target intracellular folate metabolism, such as pemetrexed and methotrexate. Folate is taken up by the cell via this receptor, which also targeted by many cancer agents due to the over-expression of the receptor by cancer cells. FR is a membrane-bound glycosyl-phosphatidylinositol (GPI) anchor glycoprotein encoded by the folate receptor 1 (FOLR1) gene. FR plays a significant role in DNA synthesis, cell proliferation, DNA repair, and intracellular signaling, all of which are essential for tumorigenesis. FR is more prevalent in cancer cells compared to normal tissues, which makes it an excellent target for oncologic therapeutics. FRα is found in many cancer types, including ovarian cancer, non-small-cell lung cancer (NSCLC), and colon cancer. FR is widely used in antibody drug conjugates, small-molecule-drug conjugates, and chimeric antigen-receptor T cells. Current oncolytic therapeutics include mirvetuximab soravtansine, and ongoing clinical trials are underway to investigate chimeric antigen receptor T cells (CAR-T cells) and vaccines. Additionally, FRα has been used in a myriad of other applications, including as a tool in the identification of tumor types, and as a prognostic marker, as a surrogate of chemotherapy resistance. As such, FRα identification has become an essential part of precision medicine.
Collapse
Affiliation(s)
- Teresita Gonzalez
- Memorial Cancer Institute, Pembroke Pines, FL 33028, USA; (M.M.); (O.N.); (M.V.)
| | | | | | | |
Collapse
|
|
9
|
Li K, You G, Jiang K, Wang R, Li W, Meng Y, Fang Y, Chen W, Zhu G, Song J, Wang W, Su H, Hu B, Sun F, Jia Z, Li C, Zhu J. Root extract of Hemsleya amabilis Diels suppresses renal cell carcinoma cell growth through inducing apoptosis and G 2/M phase arrest via PI3K/AKT signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117014. [PMID: 37557938 DOI: 10.1016/j.jep.2023.117014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/16/2023] [Accepted: 08/07/2023] [Indexed: 08/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hemsleya amabilis Diels, belongs to cucurbitaceae, was traditional Chinese medicine (TCM). It is widely used to treat various diseases. However, these diseases may contribute to the development of RCC. AIM OF THE STUDY investigated the anticancer activities of root extract of Hemsleya amabilis Diels (HRE), and elucidated the underlying molecular mechanism in vivo and in vitro. MATERIALS AND METHODS Dried Hemsleya amabilis Diels roots were extracted by ethyl acetate and used to treat RCC4, OS-RC-2 and ACHN cells. UHPLC-MS was used to analyze the chemical composition of the extract. CCK-8 and colony formation assay were used to investigate proliferation. PI staining was used to detect cell cycle. Annexin-V-FITC, AO/EB and TEM were used to evaluate apoptosis. Transwell and wound healing assays were used to evaluate migration and invasion. RNA-seq, Network pharmacology, autodocking for virtual screening and molecular dynamics simulation were used to analyze potential molecular mechanisms and active components of HRE inhibiting proliferation of RCC. LY294002 and UC2288 were used to inhibit PI3K and P21 expression, respectively. IGF-1 was used to activate PI3K. Xenograft tumor model was established to evaluate its anti-tumor potential in vivo. Immunohistochemistry and Western blot were used to test protein expression levels. H&E staining was used to explore the side effects of HRE in vivo. Applying bioinformatics to analyze the effect of P21 on RCC. RESULTS HRE consists of 739 compounds. CCK-8 and colony formation assay showed that HRE significantly inhibited RCC cells proliferation. PI staining indicated that HRE caused G2/M phase arrest. Annexin-V-FITC, AO/EB and TEM experiments revealed that HRE significantly promoted apoptosis of RCC cells. Transwell and wound healing assays showed that HRE can inhibit the migration and invasion of RCC cells. RNA-seq showed that HRE induced 230 gene changes. Network pharmacology analysis found the relationship between HRE-component-target-RCC. Auto-docking found that Epitulipinolide diepoxide in HRE can stably bind to PIK3CA (-7.22 kJ/mol), and molecular dynamics simulation verified the combination between Epitulipinolide diepoxide of PIK3CA. In RCC4 cells, pretreatment with IGF-1, attenuated HRE-induced apoptosis and G2/M arrest. When pretreated with PIK3 inhibitor LY294002, the opposite result appears. Pretreatment with CDKN1A (P21) inhibitor UC2288 attenuated HRE-induced G2/M arrest. Xenograft tumor model showed that HRE inhibited tumor growth. Western blot analysis indicated that HRE can regulating Bax, Bcl-2, PARP, cleared-PARP, Caspase-9, Caspase-8, Caspase-3, Survivin, Cyclin-B1, CDK1, N-cadherin, snail, slug, E-cadherin, MMP-9. Immunohistochemical staining showed that in the treated group, expression of E-cadherin, Bax, P21 was up-regulated, while N-cadherin, PI3K, AKT and Bcl-2 were down-regulated. H&E staining showed that compared to control groups, the main organs in the HRE-treated groups showed no histological abnormalities. The overall survival rate of RCC patients in the high-expression group of P21 was higher than in the low-expression group of P21 on bioinformatics analysis. CONCLUSIONS HRE inhibited RCC migration and invasion through EMT, and inhibited proliferation in vivo and in vitro. In addition, HRE inhibited proliferation through promoting apoptosis and P21-induced G2/M phase arrest via PI3K/AKT signaling pathway. Overall, these results suggest that HRE may be a promising chemotherapy agent for RCC.
Collapse
Affiliation(s)
- Kai Li
- Guizhou Provincial Key Laboratory for Rare Animal and Economic Insect of the Mountainous Region, College of Biology and Environmental Engineering, Guiyang University, Guiyang, 550025, China
| | - Ganhua You
- The Second People's Hospital of Guizhou Province, Guiyang, 550002, China
| | - Kehua Jiang
- Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China
| | - Rongpin Wang
- Department of Radiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, 550002, China
| | - Wuchao Li
- Department of Radiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, 550002, China
| | - Yonglu Meng
- Guizhou Provincial Key Laboratory for Rare Animal and Economic Insect of the Mountainous Region, College of Biology and Environmental Engineering, Guiyang University, Guiyang, 550025, China
| | - Yinyi Fang
- Medical College of Guizhou University, Guiyang, Guizhou Province, 550025, China
| | - Weiming Chen
- Medical College of Guizhou University, Guiyang, Guizhou Province, 550025, China
| | - Guohua Zhu
- Department of Pedictric, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China
| | - Jukun Song
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, China
| | - Wei Wang
- Department of Pedictric, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China
| | - Hao Su
- Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China
| | - Bin Hu
- Department of Urology, Kweichow Moutai Hospital, Renhuai, China
| | - Fa Sun
- Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China.
| | - Zhenyu Jia
- University of California of Riverside, Riverside, CA, 92521, USA.
| | - Can Li
- Guizhou Provincial Key Laboratory for Rare Animal and Economic Insect of the Mountainous Region, College of Biology and Environmental Engineering, Guiyang University, Guiyang, 550025, China.
| | - Jianguo Zhu
- Guizhou Provincial Key Laboratory for Rare Animal and Economic Insect of the Mountainous Region, College of Biology and Environmental Engineering, Guiyang University, Guiyang, 550025, China; Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China.
| |
Collapse
|
|
10
|
Zhao H, Bi F, Li M, Diao Y, Zhang C. E3 ubiquitin ligase RNF180 impairs IPO4/SOX2 complex stability and inhibits SOX2-mediated malignancy in ovarian cancer. Cell Signal 2024; 113:110961. [PMID: 37923100 DOI: 10.1016/j.cellsig.2023.110961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 10/17/2023] [Accepted: 10/30/2023] [Indexed: 11/07/2023]
Abstract
RING finger protein 180 (RNF180), an E3 ubiquitin ligase, is thought to be a tumor suppressor gene. However, the detailed mechanism of its effect on ovarian cancer (OV) has not been elucidated. Importin 4 (IPO4) which belongs to transport protein is reported to have cancer-promoting effects on OV. Here, we explored the potential signaling pathways related to RNF180 and IPO4. It was first verified that RNF180 is downregulated and IPO4 is upregulated in OV. By overexpressing or knocking down RNF180 in OV cells, we confirmed that RNF180 inhibited the malignant behaviors of OV cells both in vitro and in vivo. Bioinformatics analysis and proteomics experiments found that RNF180 could interact with IPO4 and promote the degradation of IPO4 through ubiquitination. In addition, overexpression of IPO4 removed the inhibitory effect of RNF180 on OV. We subsequently found that IPO4 could bind to the oncogene Sex determining Region Y-box 2 (SOX2). Knockdown of IPO4 in OV cells decreased SOX2 protein level in nucleus and promoted cyclin-dependent kinase inhibitory protein-1 (p21) expression. Overexpression of RNF180 also inhibited the expression of SOX2 in nucleus. All these results indicated that RNF180 inhibited the nuclear translocation of SOX2 by promoting ubiquitination of IPO4, which ultimately promoted the expression of p21 and then suppressed the progression of OV. This study verified the tumor suppressor effect of RNF180 on OV, elucidated the mechanism of the molecule network related to RNF180 and IPO4 in OV and identified for OV.
Collapse
Affiliation(s)
- Haiyan Zhao
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fangfang Bi
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Mengyuan Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuhan Diao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chen Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| |
Collapse
|
|
11
|
Lei N, Lei LL, Wang CH, Mei CR. Pure testicular choriocarcinoma, a rare and highly malignant subtype with challenging treatment: A case report and review of the literature. Mol Clin Oncol 2024; 20:1. [PMID: 38223403 PMCID: PMC10784770 DOI: 10.3892/mco.2023.2699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 10/26/2023] [Indexed: 01/16/2024] Open
Abstract
Testicular choriocarcinoma (CC) is the rarest subtype of germ cell tumours (GCTs) of the testis, with a high malignant potential and early haematogenous metastasis. Radical surgical resection should be performed primarily for histological diagnosis, while chemotherapy remains the mainstay of therapy for advanced disease. In the present study, the case of a 65-year-old male patient diagnosed with metastatic testicular CC, who did not fully respond to chemotherapy is reported. This patient underwent surgical removal of the testicular tumour, chemotherapy with etoposide and cisplatin, and radiotherapy of the intracranial lesions. Although the serum human chorionic gonadotropin (HCG) levels of the patient and most of the metastases continued decreasing during chemotherapy, complete response was not achieved after six cycles of chemotherapy. The patient refused high-dose chemotherapy and autologous stem cell transplantation due to severe side effects, and eventually developed respiratory failure on maintenance therapy with oral etoposide. A literature review was then performed, aiming to summarize the characteristics and therapeutic principles of testicular CC. In addition, the emerging therapeutic agents that could be used in maintenance therapy for GCTs, particularly for testicular CC, were also discussed. The limited clinical trials of targeted treatments showed potential benefit for long survival of patients with selected GCTs with fewer side effects. In particular, immunotherapy showed unique potential for testicular CC in preclinical studies, offering new approaches of maintenance therapy for advanced disease. Further studies should shed light on the identification of prognostic factors that predict the response to immune-based therapy in GCTs.
Collapse
Affiliation(s)
- Na Lei
- Department of Medical Oncology, Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region (Hospital. C. T.), Chengdu, Sichuan 610041, P.R. China
| | - Li-Li Lei
- Department of Medical Oncology, Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region (Hospital. C. T.), Chengdu, Sichuan 610041, P.R. China
| | - Chao-Hong Wang
- Department of Medical Oncology, Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region (Hospital. C. T.), Chengdu, Sichuan 610041, P.R. China
| | - Chao-Rong Mei
- Department of Medical Oncology, Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region (Hospital. C. T.), Chengdu, Sichuan 610041, P.R. China
| |
Collapse
|
|
12
|
Zihlif M, Hameduh T, Bulatova N, Hammad H. Alteration in the expression of the chemotherapy resistance‑related genes in response to chronic and acute hypoxia in pancreatic cancer. Biomed Rep 2023; 19:88. [PMID: 37901880 PMCID: PMC10603373 DOI: 10.3892/br.2023.1670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 09/08/2023] [Indexed: 10/31/2023] Open
Abstract
Pancreatic cancer is currently one of the least curable types of human cancer and remains a key health problem. One of the most important characteristics of pancreatic cancer is its ability to grow under hypoxic conditions. Hypoxia is associated with resistance of cancer cells to radiotherapy and chemotherapy. It is a major contributor to pancreatic cancer genetic instability, which local and systemic resistance that may result in poor clinical outcome. Accordingly, identifying gene expression changes in cancer resistance genes that occur under hypoxic conditions may identify a new therapeutic target. The aim of the present study was to explore the association between hypoxia and resistance to chemotherapy and determine the alteration in the expression of cancer resistance-related genes in the presence of hypoxia. Pancreatic cancer cells (PANC-1) were exposed to 8 h hypoxic episodes (<1% oxygen) three times/week for a total of 20 episodes (chronic hypoxia) or 72 h hypoxic episodes twice/week for a total of 10 episodes (acute hypoxia). The alterations in gene expression were examined using reverse transcription-quantitative PCR array compared with normoxic cells. Chemoresistance of hypoxic cells toward doxorubicin was assessed using MTT cell proliferation assay. Both chronic and acute hypoxia induced chemoresistance toward doxorubicin in PANC-1 pancreatic cancer cell line. The greatest changes occurred in estrogen Receptor Alpha Gene (ESR1) and ETS Like-1 protein (ELK1) pathways, in nucleic transcription factor Peroxisome proliferator-activated receptors (PPARs) and in a cell cycle inhibitor cyclin dependent kinase inhibitor 1A (CDKN1A). The present study demonstrated that exposing cells to prolonged hypoxia results in different gene expression changes involving pleotropic pathways that serve a role in inducing resistance in pancreatic cancer.
Collapse
Affiliation(s)
- Malek Zihlif
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Tareq Hameduh
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Nailya Bulatova
- Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Hana Hammad
- Department of Biology, School of Science, The University of Jordan, Amman 11942, Jordan
| |
Collapse
|
|
13
|
Fu T, Ma X, Du SL, Ke ZY, Wang XC, Yin HH, Wang WX, Liu YJ, Liang AL. p21 promotes gemcitabine tolerance in A549 cells by inhibiting DNA damage and altering the cell cycle. Oncol Lett 2023; 26:471. [PMID: 37809050 PMCID: PMC10551858 DOI: 10.3892/ol.2023.14059] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 09/01/2023] [Indexed: 10/10/2023] Open
Abstract
Gemcitabine is one of the most widely used chemotherapy drugs for advanced malignant tumors, including non-small cell lung cancer. However, the clinical efficacy of gemcitabine is limited due to drug resistance. The aim of the present study was to investigate the role of p21 in gemcitabine-resistant A549 (A549/G+) lung cancer cells. IC50 values were determined using a Cell Counting Kit-8 (CCK-8) assay. mRNA and protein expression levels of genes were measured by reverse transcription-quantitative PCR and western blotting, respectively. The cell cycle distribution and apoptosis rate were analyzed by flow cytometry. DNA damage in cells was evaluated by single-cell gel electrophoresis. The results of western blot analysis and the CCK-8 assay demonstrated that the expression of p21 was higher in A549/G+ cells than in gemcitabine-sensitive cells. Knockdown of p21 expression in gemcitabine-resistant cells sensitized these cells to gemcitabine (with the IC50 decreasing from 84.2 to 26.7 µM). Cell cycle analysis revealed different changes in the cell cycle distribution in A549/G+ cells treated with the same concentration of gemcitabine, and decreased expression of p21 was shown to promote G1 arrest. The apoptosis assay and comet assay results revealed that decreased p21 expression resulted in accumulation of unrepaired DNA double-strand breaks (DSBs) and induction of apoptosis by gemcitabine. The present study demonstrated that knockout of p21 mRNA expression in A549/G+ cells promotes apoptosis and DNA DSB accumulation, accompanied by G1 arrest. These results indicated that p21 is involved in regulating the response of A549 cells to gemcitabine.
Collapse
Affiliation(s)
- Tian Fu
- Department of Biochemistry and Molecular Biology, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Biochemistry, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Laboratory, Zhanjiang Central Hospital, Zhanjiang, Guangdong 524045, P.R. China
| | - Xuan Ma
- Department of Clinical Laboratory, Xinle City Hospital, Shijiazhuang, Hebei 050700, P.R. China
| | - Shen-Lin Du
- Department of Clinical Laboratory, Dongguan People's Hospital, Dongguan, Guangdong 523058, P.R. China
| | - Zhi-Yin Ke
- Department of Biochemistry and Molecular Biology, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Biochemistry, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Xue-Chun Wang
- Department of Biochemistry and Molecular Biology, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Biochemistry, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Hai-Han Yin
- Department of Biochemistry and Molecular Biology, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Biochemistry, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Wen-Xuan Wang
- Department of Biochemistry and Molecular Biology, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Biochemistry, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Yong-Jun Liu
- Department of Biochemistry and Molecular Biology, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Biochemistry, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Ai-Ling Liang
- Department of Biochemistry and Molecular Biology, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Biochemistry, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| |
Collapse
|
|
14
|
Doghish AS, Moustafa HAM, Elballal MS, Sallam AAM, El-Dakroury WA, Abdel Mageed SS, Elesawy AE, Abdelmaksoud NM, Shahin RK, Midan HM, Elrebehy MA, Elazazy O, Nassar YA, Elazab IM, Elballal AS, Elballal MS, Abulsoud AI. The potential role of miRNAs in the pathogenesis of testicular germ cell tumors - A Focus on signaling pathways interplay. Pathol Res Pract 2023; 248:154611. [PMID: 37315401 DOI: 10.1016/j.prp.2023.154611] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/04/2023] [Accepted: 06/07/2023] [Indexed: 06/16/2023]
Abstract
Testicular germ cell tumors (TGCTs) are the most common testicular neoplasms in adolescents and young males. Understanding the genetic basis of TGCTs represents a growing need to cope with the increased incidence of these neoplasms. Although the cure rates have been comparatively increased, investigation of mechanisms underlying the incidence, progression, metastasis, recurrence, and therapy resistance is still necessary. Early diagnosis and non-compulsory clinical therapeutic agents without long-term side effects are now required to reduce the cancer burden, especially in the younger age groups. MicroRNAs (miRNAs) control an extensive range of cellular functions and exhibit a pivotal action in the development and spreading of TGCTs. Because of their dysregulation and disruption in function, miRNAs have been linked to the malignant pathophysiology of TGCTs by influencing many cellular functions involved in the disease. These biological processes include increased invasive and proliferative perspective, cell cycle dysregulation, apoptosis disruption, stimulation of angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and resistance to certain treatments. Herein, we present an up-to-date review of the biogenesis of miRNAs, miRNA regulatory mechanisms, clinical challenges, and therapeutic interventions of TGCTs, and role of nanoparticles in the treatment of TGCTs.
Collapse
Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
| | - Hebatallah Ahmed Mohamed Moustafa
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | | | - Reem K Shahin
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Yara A Nassar
- Biology Department, School of Biotechnology, Badr University in Cairo, Badr City, Cairo 11829, Egypt
| | - Ibrahim M Elazab
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - Ahmed S Elballal
- Department of Dentistry, Medical Administration, University of Sadat, City Menoufia 32897, Egypt
| | | | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| |
Collapse
|
|
15
|
Elesawy AE, Abulsoud AI, Moustafa HAM, Elballal MS, Sallam AAM, Elazazy O, El-Dakroury WA, Abdel Mageed SS, Abdelmaksoud NM, Midan HM, Shahin RK, Elrebehy MA, Nassar YA, Elazab IM, Elballal AS, Elballal MS, Doghish AS. miRNAs orchestration of testicular germ cell tumors - Particular emphasis on diagnosis, progression and drug resistance. Pathol Res Pract 2023; 248:154612. [PMID: 37327566 DOI: 10.1016/j.prp.2023.154612] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/18/2023]
Abstract
Testicular cancer (TC) is one of the most frequently incident solid tumors in males. A growing prevalence has been documented in developed countries. Although recent advances have made TC an exceedingly treatable cancer, numerous zones in TC care still have divisive treatment decisions. In addition to physical examination and imaging techniques, conventional serum tumor markers have been traditionally used for the diagnosis of testicular germ cell tumors (TGCT). Unlike other genital and urinary tract tumors, recent research methods have not been broadly used in TGCTs. Even though several challenges in TC care must be addressed, a dedicated group of biomarkers could be particularly beneficial to help classify patient risk, detect relapse early, guide surgery decisions, and tailor follow-up. Existing tumor markers (Alpha-fetoprotein, human chorionic gonadotrophin, and lactate dehydrogenase) have limited accuracy and sensitivity when used as diagnostic, prognostic, or predictive markers. At present, microRNAs (miRNA or miR) play a crucial role in the process of several malignancies. The miRNAs exhibit pronounced potential as novel biomarkers since they reveal high stability in body fluids, are easily detected, and are relatively inexpensive in quantitative assays. In this review, we aimed to shed light on the recent novelties in developing microRNAs as diagnostic and prognostic markers in TC and discuss their clinical applications in TC management.
Collapse
Affiliation(s)
- Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt.
| | - Hebatallah Ahmed Mohamed Moustafa
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | | | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Reem K Shahin
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Yara A Nassar
- Biology Department, School of Biotechnology, Badr University in Cairo, Badr City, Cairo 11829, Egypt
| | - Ibrahim M Elazab
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - Ahmed S Elballal
- Department of Dentistry, Medical Administration, University of Sadat City Menoufia 32897, Egypt
| | | | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| |
Collapse
|
|
16
|
Hassel JC, Zimmer L, Sickmann T, Eigentler TK, Meier F, Mohr P, Pukrop T, Roesch A, Vordermark D, Wendl C, Gutzmer R. Medical Needs and Therapeutic Options for Melanoma Patients Resistant to Anti-PD-1-Directed Immune Checkpoint Inhibition. Cancers (Basel) 2023; 15:3448. [PMID: 37444558 DOI: 10.3390/cancers15133448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials.
Collapse
Affiliation(s)
- Jessica C Hassel
- Skin Cancer Center, Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Lisa Zimmer
- Department of Dermatology, University Hospital Essen, 45147 Essen, Germany
- German Cancer Consortium (DKTK), Partner Site Essen, 69120 Heidelberg, Germany
| | | | - Thomas K Eigentler
- Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
| | - Friedegund Meier
- Department of Dermatology, Skin Cancer Center at the University Cancer Centre and National Center for Tumor Diseases, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01062 Dresden, Germany
| | - Peter Mohr
- Department of Dermatology, Elbe-Kliniken, 21614 Buxtehude, Germany
| | - Tobias Pukrop
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 93053 Regensburg, Germany
| | - Alexander Roesch
- Department of Dermatology, University Hospital Essen, 45147 Essen, Germany
| | - Dirk Vordermark
- Department for Radiation Oncology, Martin-Luther University Halle-Wittenberg, 06108 Halle, Germany
| | - Christina Wendl
- Department of Radiology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Ralf Gutzmer
- Department of Dermatology, Johannes Wesling Medical Center, Ruhr University Bochum, 32429 Minden, Germany
| |
Collapse
|
|
17
|
Krishnaraj J, Yamamoto T, Ohki R. p53-Dependent Cytoprotective Mechanisms behind Resistance to Chemo-Radiotherapeutic Agents Used in Cancer Treatment. Cancers (Basel) 2023; 15:3399. [PMID: 37444509 DOI: 10.3390/cancers15133399] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Resistance to chemoradiotherapy is the main cause of cancer treatment failure. Cancer cells, especially cancer stem cells, utilize innate cytoprotective mechanisms to protect themselves from the adverse effects of chemoradiotherapy. Here, we describe a few such mechanisms: DNA damage response (DDR), immediate early response gene 5 (IER5)/heat-shock factor 1 (HSF1) pathway, and p21/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which are regulated by the tumour suppressor p53. Upon DNA damage caused during chemoradiotherapy, p53 is recruited to the sites of DNA damage and activates various DNA repair enzymes including GADD45A, p53R2, DDB2 to repair damaged-DNA in cancer cells. In addition, the p53-IER5-HSF1 pathway protects cancer cells from proteomic stress and maintains cellular proteostasis. Further, the p53-p21-NRF2 pathway induces production of antioxidants and multidrug resistance-associated proteins to protect cancer cells from therapy-induced oxidative stress and to promote effusion of drugs from the cells. This review summarises possible roles of these p53-regulated cytoprotective mechanisms in the resistance to chemoradiotherapy.
Collapse
Affiliation(s)
- Jayaraman Krishnaraj
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
| | - Tatsuki Yamamoto
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
| | - Rieko Ohki
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
| |
Collapse
|
|
18
|
Tóthová Z, Šemeláková M, Bhide K, Bhide M, Kováč A, Majerová P, Kvaková M, Štofilová J, Solárová Z, Solár P. Differentially Expressed Genes Induced by Erythropoietin Receptor Overexpression in Rat Mammary Adenocarcinoma RAMA 37-28 Cells. Int J Mol Sci 2023; 24:ijms24108482. [PMID: 37239828 DOI: 10.3390/ijms24108482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/25/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
The erythropoietin receptor (EPOR) is a transmembrane type I receptor with an essential role in the proliferation and differentiation of erythroid progenitors. Besides its function during erythropoiesis, EPOR is expressed and has protective effect in various non-hematopoietic tissues, including tumors. Currently, the advantageous aspect of EPOR related to different cellular events is still under scientific investigation. Besides its well-known effect on cell proliferation, apoptosis and differentiation, our integrative functional study revealed its possible associations with metabolic processes, transport of small molecules, signal transduction and tumorigenesis. Comparative transcriptome analysis (RNA-seq) identified 233 differentially expressed genes (DEGs) in EPOR overexpressed RAMA 37-28 cells compared to parental RAMA 37 cells, whereas 145 genes were downregulated and 88 upregulated. Of these, for example, GPC4, RAP2C, STK26, ZFP955A, KIT, GAS6, PTPRF and CXCR4 were downregulated and CDH13, NR0B1, OCM2, GPM6B, TM7SF3, PARVB, VEGFD and STAT5A were upregulated. Surprisingly, two ephrin receptors, EPHA4 and EPHB3, and EFNB1 ligand were found to be upregulated as well. Our study is the first demonstrating robust differentially expressed genes evoked by simple EPOR overexpression without the addition of erythropoietin ligand in a manner which remains to be elucidated.
Collapse
Affiliation(s)
- Zuzana Tóthová
- Department of Medical Biology, Faculty of Medicine, P.J. Šafárik University in Košice, 04001 Košice, Slovakia
| | - Martina Šemeláková
- Department of Medical Biology, Faculty of Medicine, P.J. Šafárik University in Košice, 04001 Košice, Slovakia
| | - Katarína Bhide
- Laboratory of Biomedical Microbiology and Immunology, University of Veterinary Medicine and Pharmacy in Košice, 04001 Košice, Slovakia
| | - Mangesh Bhide
- Laboratory of Biomedical Microbiology and Immunology, University of Veterinary Medicine and Pharmacy in Košice, 04001 Košice, Slovakia
- Institute of Neuroimmunology, Slovak Academy of Sciences, 84510 Bratislava, Slovakia
| | - Andrej Kováč
- Institute of Neuroimmunology, Slovak Academy of Sciences, 84510 Bratislava, Slovakia
| | - Petra Majerová
- Institute of Neuroimmunology, Slovak Academy of Sciences, 84510 Bratislava, Slovakia
| | - Monika Kvaková
- Department of Experimental Medicine, Faculty of Medicine, P.J. Šafárik University in Košice, 04001 Košice, Slovakia
| | - Jana Štofilová
- Department of Experimental Medicine, Faculty of Medicine, P.J. Šafárik University in Košice, 04001 Košice, Slovakia
| | - Zuzana Solárová
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University in Košice, 04001 Košice, Slovakia
| | - Peter Solár
- Department of Medical Biology, Faculty of Medicine, P.J. Šafárik University in Košice, 04001 Košice, Slovakia
| |
Collapse
|
|
19
|
Váncza L, Horváth A, Seungyeon L, Rókusz A, Dezső K, Reszegi A, Petővári G, Götte M, Kovalszky I, Baghy K. SPOCK1 Overexpression Suggests Poor Prognosis of Ovarian Cancer. Cancers (Basel) 2023; 15:cancers15072037. [PMID: 37046698 PMCID: PMC10093273 DOI: 10.3390/cancers15072037] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/20/2023] [Accepted: 03/26/2023] [Indexed: 04/03/2023] Open
Abstract
Purpose: Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been found in a variety of malignant tumors and is associated with a poor prognosis. We aimed to explore the role of SPOCK1 in ovarian cancer. Methods: Ovarian cancer cell lines SKOV3 and SW626 were transfected with SPOCK1 overexpressing or empty vector using electroporation. Cells were studied by immunostaining and an automated Western blotting system. BrdU uptake and wound healing assays assessed cell proliferation and migration. SPOCK1 expression in human ovarian cancer tissues and in blood samples were studied by immunostaining and ELISA. Survival of patients with tumors exhibiting low and high SPOCK1 expression was analyzed using online tools. Results: Both transfected cell lines synthesized different SPOCK1 variants; SKOV3 cells also secreted the proteoglycan. SPOCK1 overexpression stimulated DNA synthesis and cell migration involving p21CIP1. Ovarian cancer patients had increased SPOCK1 serum levels compared to healthy controls. Tumor cells of tissues also displayed abundant SPOCK1. Moreover, SPOCK1 levels were higher in untreated ovarian cancer serum and tissue samples and lower in recipients of chemotherapy. According to in silico analyses, high SPOCK1 expression was correlated with shorter survival. Conclusion: Our findings suggest SPOCK1 may be a viable anti-tumor therapeutic target and could be used for monitoring ovarian cancer.
Collapse
|
|
20
|
Skowron MA, Kotthoff M, Bremmer F, Ruhnke K, Parmaksiz F, Richter A, Küffer S, Reuter-Jessen K, Pauls S, Stefanski A, Ströbel P, Stühler K, Nettersheim D. Targeting CLDN6 in germ cell tumors by an antibody-drug-conjugate and studying therapy resistance of yolk-sac tumors to identify and screen specific therapeutic options. Mol Med 2023; 29:40. [PMID: 36991316 PMCID: PMC10053054 DOI: 10.1186/s10020-023-00636-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 03/13/2023] [Indexed: 03/31/2023] Open
Abstract
BACKGROUND Being the standard-of-care for four decades, cisplatin-based chemotherapy is highly efficient in treating germ cell tumors (GCT). However, often refractory patients present with a remaining (resistant) yolk-sac tumor (YST(-R)) component, resulting in poor prognosis due to lack of novel treatment options besides chemotherapy and surgery. The aim of this study was to identify novel targets for the treatment of YST by deciphering the molecular mechanisms of therapy resistance. Additionally, we screened the cytotoxic efficacy of a novel antibody-drug-conjugate targeting CLDN6 (CLDN6-ADC), as well as pharmacological inhibitors to target specifically YST. METHODS Protein and mRNA levels of putative targets were measured by flow cytometry, immunohistochemical stainings, mass spectrometry of formalin-fixed paraffin-embedded tissues, phospho-kinase arrays, or qRT-PCR. Cell viability, apoptosis and cell cycle assays of GCT and non-cancerous cells were performed using XTT cell viability assays or Annexin V / propidium iodide flow cytometry, respectively. Druggable genomic alterations of YST(-R) tissues were identified by the TrueSight Oncology 500 assay. RESULTS We demonstrated that treatment with a CLDN6-ADC enhanced apoptosis induction specifically in CLDN6+ GCT cells in comparison with non-cancerous controls. In a cell line-dependent manner, either an accumulation in the G2 / M cell cycle phase or a mitotic catastrophe was observed. Based on mutational and proteome profiling, this study identified drugs targeting the FGF, VGF, PDGF, mTOR, CHEK1, AURKA, or PARP signaling pathways as promising approaches to target YST. Further, we identified factors relevant for MAPK signaling, translational initiation and RNA binding, extracellular matrix-related processes as well as oxidative stress and immune response to be involved in therapy resistance. CONCLUSIONS In summary, this study offers a novel CLDN6-ADC to target GCT. Additionally, this study presents novel pharmacological inhibitors blocking FGF, VGF, PDGF, mTOR, CHEK1, AURKA, or PARP signaling for the treatment of (refractory) YST patients. Finally, this study shed light on the mechanisms of therapy resistance in YST.
Collapse
Affiliation(s)
- Margaretha A Skowron
- Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Mara Kotthoff
- Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Felix Bremmer
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Katja Ruhnke
- Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Fatma Parmaksiz
- Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Annika Richter
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Stefan Küffer
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | | | - Stella Pauls
- Molecular Proteomics Laboratory, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Anja Stefanski
- Molecular Proteomics Laboratory, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Philipp Ströbel
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Kai Stühler
- Molecular Proteomics Laboratory, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Daniel Nettersheim
- Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.
| |
Collapse
|
|
21
|
Na Y, Hall A, Yu Y, Hu L, Choi K, Burgard JA, Szabo S, Huang G, Ratner N, Wu J. Runx1/3-driven adaptive endoplasmic reticulum stress pathways contribute to neurofibromagenesis. Oncogene 2023; 42:1038-1047. [PMID: 36759572 PMCID: PMC10194627 DOI: 10.1038/s41388-023-02620-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 01/28/2023] [Accepted: 01/31/2023] [Indexed: 02/11/2023]
Abstract
Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.
Collapse
Affiliation(s)
- Youjin Na
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Ashley Hall
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Yanan Yu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
- College of Life Science, Xuzhou Medical University, 221004, Jiangsu, P. R. China
| | - Liang Hu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Kwangmin Choi
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Jake A Burgard
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Sara Szabo
- Department of Pediatrics and Department of Pediatric Pathology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Gang Huang
- Department of Cell Systems & Anatomy and Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, USA
- Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, 78229, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Jianqiang Wu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
| |
Collapse
|
|
22
|
SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation. Cancers (Basel) 2023; 15:cancers15030905. [PMID: 36765862 PMCID: PMC9913612 DOI: 10.3390/cancers15030905] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/25/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases.
Collapse
|
|
23
|
Friedlová N, Zavadil Kokáš F, Hupp TR, Vojtěšek B, Nekulová M. IFITM protein regulation and functions: Far beyond the fight against viruses. Front Immunol 2022; 13:1042368. [PMID: 36466909 PMCID: PMC9716219 DOI: 10.3389/fimmu.2022.1042368] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/27/2022] [Indexed: 07/30/2023] Open
Abstract
Interferons (IFNs) are important cytokines that regulate immune responses through the activation of hundreds of genes, including interferon-induced transmembrane proteins (IFITMs). This evolutionarily conserved protein family includes five functionally active homologs in humans. Despite the high sequence homology, IFITMs vary in expression, subcellular localization and function. The initially described adhesive and antiproliferative or pro-oncogenic functions of IFITM proteins were diluted by the discovery of their antiviral properties. The large set of viruses that is inhibited by these proteins is constantly expanding, as are the possible mechanisms of action. In addition to their beneficial antiviral effects, IFITM proteins are often upregulated in a broad spectrum of cancers. IFITM proteins have been linked to most hallmarks of cancer, including tumor cell proliferation, therapeutic resistance, angiogenesis, invasion, and metastasis. Recent studies have described the involvement of IFITM proteins in antitumor immunity. This review summarizes various levels of IFITM protein regulation and the physiological and pathological functions of these proteins, with an emphasis on tumorigenesis and antitumor immunity.
Collapse
Affiliation(s)
- Nela Friedlová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
| | - Filip Zavadil Kokáš
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
| | - Ted R. Hupp
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Bořivoj Vojtěšek
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
| | - Marta Nekulová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
| |
Collapse
|
|
24
|
Blessing WA, Digesu CS, Liu R, Mahvi DA, Tal-Mason A, Kumar A, Hachey KJ, Colby AH, Korunes-Miller JT, Agar N, Regan MS, Shih A, Raut CP, Grinstaff MW, Colson YL. Sustained Supratherapeutic Paclitaxel Delivery Enhances Irreversible Sarcoma Cell Death. Mol Cancer Ther 2022; 21:1663-1673. [PMID: 36031342 PMCID: PMC9633561 DOI: 10.1158/1535-7163.mct-21-0750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 05/26/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022]
Abstract
Risk of locoregional recurrence after sarcoma resection is high, increasing both morbidity and mortality. Intraoperative implantation of paclitaxel (PTX)-eluting polymer films locally delivers sustained, supratherapeutic PTX concentrations to the tumor bed that are not clinically feasible with systemic therapy, thereby reducing recurrence and improving survival in a murine model of recurrent sarcoma. However, the biology underlying increased efficacy of PTX-eluting films is unknown and provides the impetus for this work. In vitro PTX efficacy is time and dose dependent with prolonged exposure significantly decreasing PTX IC50 values for human chondrosarcoma (CS-1) cells (153.9 nmol/L at 4 hours vs. 14.2 nmol/L at 30 hours, P = 0.0001). High-dose PTX significantly inhibits proliferation with in vivo PTX films delivering a dose >130 μmol/L directly to the tumor thereby irreversibly arresting cell cycle and inducing apoptosis in CS-1 as well as patient-derived liposarcoma (LP6) and leiomyosarcoma (LMS20). Supratherapeutic PTX upregulates the expression of p21 in G2-M arrested cells, and irreversibly induces apoptosis followed by cell death, within 4 hours of exposure. Microarray analyses corroborate the finding of poor DNA integrity commonly observed as a final step of apoptosis in CS-1 cells and tumor. Unlike low PTX concentrations at the tumor bed during systemic delivery, supratherapeutic concentrations achieved with PTX-eluting films markedly decrease sarcoma lethality in vivo and offer an alternative paradigm to prevent recurrence.
Collapse
Affiliation(s)
- William A. Blessing
- Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Christopher S. Digesu
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Rong Liu
- Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - David A. Mahvi
- Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Aya Tal-Mason
- Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Anil Kumar
- Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | - Aaron H. Colby
- Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA
| | - Jenny T. Korunes-Miller
- Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA
| | - Natalie Agar
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Michael S. Regan
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Angela Shih
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Chandrajit P. Raut
- Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Mark W. Grinstaff
- Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA
| | - Yolonda L. Colson
- Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| |
Collapse
|
|
25
|
Sorteberg AL, Halipi V, Wickström M, Shirazi Fard S. The cyclin dependent kinase inhibitor p21Cip1/Waf1 is a therapeutic target in high-risk neuroblastoma. Front Oncol 2022; 12:906194. [PMID: 36147919 PMCID: PMC9486206 DOI: 10.3389/fonc.2022.906194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/02/2022] [Indexed: 11/29/2022] Open
Abstract
Platinum-based chemotherapies such as cisplatin are used as first-line treatment for the paediatric tumour neuroblastoma. Although the majority of neuroblastoma tumours respond to therapy, there is a high fraction of high-risk neuroblastoma patients that eventually relapse with increased resistance. Here, we show that one key determinant of cisplatin sensitivity is phosphorylation of the cyclin-dependent kinase inhibitor p21Cip1/Waf1. A panel of eight neuroblastoma cell lines and a TH-MYCN mouse model were investigated for the expression of p21Cip1/Waf1 using RT-qPCR, Western blot, and immunofluorescence. This was followed by investigation of sensitivity towards cisplatin and the p21Cip1/Waf1 inhibitor UC2288. Whereas the cell lines and the mouse model showed low levels of un-phosphorylated p21Cip1/Waf1, the phosphorylated p21Cip1/Waf1 (Thr145) was highly expressed, which in the cell lines correlated to cisplatin resistance. Furthermore, the neuroblastoma cell lines showed high sensitivity to UC2288, and combination treatment with cisplatin resulted in considerably decreased cell viability and delay in regrowth in the two most resistant cell lines, SK-N-DZ and BE(2)-C. Thus, targeting p21Cip1/Waf1 can offer new treatment strategies and subsequently lead to the design of more efficient combination treatments for high-risk neuroblastoma.
Collapse
|
|
26
|
Torres P, Anerillas C, Ramírez-Núñez O, Fernàndez A, Encinas M, Povedano M, Andrés-Benito P, Ferrer I, Ayala V, Pamplona R, Portero-Otín M. The motor neuron disease mouse model hSOD1-G93A shows a non-canonical profile of senescence biomarkers. Dis Model Mech 2022; 15:276182. [PMID: 35916061 PMCID: PMC9459393 DOI: 10.1242/dmm.049059] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/26/2022] [Indexed: 11/20/2022] Open
Abstract
To evaluate senescence mechanisms, including senescence-associated secretory phenotype (SASP), in the motor-neuron disease model hSOD1-G93A, we quantified the expression of p16 and p21 and the senescence-associated β galactosidase (SA-β-gal) in nervous tissue. As SASP markers, we measured the mRNA levels of Il1a, Il6, Ifna, and Ifnb. Furthermore, we explored if an alteration of alternative splicing is associated with senescence by measuring the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR-DNA binding of 43 kDa (Tdp-43). Transgenic mice show an atypical senescence profile with high p16 and p21 mRNA and protein in glia, without the canonical increase in SA-β-gal activity. Consistent with SASP, there is an increase in Il1a and Il6 expression, associated with increased TNFR and M-CSF protein levels, with females being partially protected. TDP-43 splicing activity is compromised in this model. Senolytic drug Navitoclax does not alter the present 'model's disease progression. This lack of effect is reproduced in vitro, in contrast with Dasatinib and quercetin, which diminish p16 and p21. Our findings show a non-canonical profile of senescence biomarkers in the model hSOD1-G93A.
Collapse
Affiliation(s)
- Pascual Torres
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Lleida, Spain
| | - Carlos Anerillas
- Oncogenic Signalling and Development, Department of Experimental Medicine, University of Lleida-IRBLleida, Lleida, Spain
| | - Omar Ramírez-Núñez
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Lleida, Spain
| | - Anna Fernàndez
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Lleida, Spain
| | - Mario Encinas
- Oncogenic Signalling and Development, Department of Experimental Medicine, University of Lleida-IRBLleida, Lleida, Spain
| | - Mònica Povedano
- Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain
| | - Pol Andrés-Benito
- Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain
| | - Isidre Ferrer
- Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain.,Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Hospitalet de Llobregat, Spain
| | - Victòria Ayala
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Lleida, Spain
| | - Reinald Pamplona
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Lleida, Spain
| | - Manuel Portero-Otín
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Lleida, Spain
| |
Collapse
|
|
27
|
miR-6077 promotes cisplatin/pemetrexed resistance in lung adenocarcinoma via CDKN1A/cell cycle arrest and KEAP1/ferroptosis pathways. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 28:366-386. [PMID: 35505963 PMCID: PMC9035384 DOI: 10.1016/j.omtn.2022.03.020] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 03/27/2022] [Indexed: 01/18/2023]
Abstract
Lung adenocarcinoma (LUAD) is one of the most common malignancies worldwide. Combination chemotherapy with cisplatin (CDDP) plus pemetrexed (PEM) remains the predominant therapeutic regimen; however, chemoresistance greatly limits its curative potential. Here, through CRISPR-Cas9 screening, we identified miR-6077 as a key driver of CDDP/PEM resistance in LUAD. Functional experiments verified that ectopic overexpression of miR-6077 desensitized LUAD cells to CDDP/PEM in both cell lines and patient-derived xenograft models. Through RNA sequencing in cells and single-cell sequencing of samples from patients with CDDP/PEM treatments, we observed CDDP/PEM-induced upregulation of CDKN1A and KEAP1, which in turn activated cell-cycle arrest and ferroptosis, respectively, thus leading to cell death. Through miRNA pull-down, we identified and validated that miR-6077 targets CDKN1A and KEAP1. Furthermore, we demonstrated that miR-6077 protects LUAD cells from cell death induced by CDDP/PEM via CDKN1A-CDK1-mediated cell-cycle arrest and KEAP1-NRF2-SLC7A11/NQO1-mediated ferroptosis, thus resulting in chemoresistance in multiple LUAD cells both in vitro and in vivo. Moreover, we found that GMDS-AS1 and LINC01128 sensitized LUAD cells to CDDP/PEM by sponging miR-6077. Collectively, these results imply the critical role of miR-6077 in LUAD’s sensitivity to CDDP/PEM, thus providing a novel therapeutic strategy for overcoming chemoresistance in clinical practice.
Collapse
|
|
28
|
Ciou HH, Lee TH, Wang HC, Ding YR, Tseng CJ, Wang PH, Tsai MH, Tzeng SL. Repurposing gestrinone for tumor suppressor through P21 reduction regulated by JNK in gynecological cancer. Transl Res 2022; 243:21-32. [PMID: 34921996 DOI: 10.1016/j.trsl.2021.12.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 11/23/2021] [Accepted: 12/06/2021] [Indexed: 11/19/2022]
Abstract
Endometriosis has been shown to increase the risk of gynecological cancers. However, the effect of gestrinone, a clinical endometriosis drug, on gynecological cancers remains unclear. This study aimed to understand the effect of gestrinone on gynecological cancers. A retrospective study was conducted using the Longitudinal Health Insurance Database 2000 of the Taiwan National Health Insurance Research Database (NHIRD) to observe the risk of gynecological cancers. Medication records from the Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital CSMUH and cancer records from the Taiwan Cancer Registry were collected to analyze the correlation between gestrinone use and gynecological cancers. Subsequently, human cell lines were used to investigate the effect of gestrinone on gynecological cancers. A total of 8330 endometriosis patients were enrolled, and analyses revealed that endometriosis patients had a higher risk of developing ovarian and endometrial cancer. However, the rate of cervical cancer was not statistically different (P = 0.249). Analyses of both the NHIRD and CSMUH databases revealed that gestrinone may reduce the risk of gynecological cancer. Cellular experiments verified the anticancer effects of gestrinone, which effectively and specifically inhibited the growth of HeLa cervical cancer cells, decreased P21 expression via JNK phosphorylation, and induced apoptosis. Combining the results of clinical database analysis and cell experiments, our findings prove that gestrinone has the potential to protect against cancer through regulation of the JNK-P21 axis. Repurposing the anticancer efficacy of gestrinone may be a strategy for targeted therapy in the future.
Collapse
Affiliation(s)
- Huai-How Ciou
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
| | - Tsung-Hsien Lee
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan; Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40203, Taiwan
| | - Hsin-Chieh Wang
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
| | - You-Ren Ding
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
| | - Chih-Jen Tseng
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40203, Taiwan; Medical Information Department, Chung Shan Medical University Hospital, Taichung 40203, Taiwan; School of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
| | - Po-Hui Wang
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan; Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40203, Taiwan
| | - Meng-Hsiun Tsai
- Department of Management Information Systems, National Chung Hsing University, Taichung 40227, Taiwan; Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 40227, Taiwan
| | - Shu-Ling Tzeng
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40203, Taiwan.
| |
Collapse
|
|
29
|
Országhová Z, Kalavska K, Mego M, Chovanec M. Overcoming Chemotherapy Resistance in Germ Cell Tumors. Biomedicines 2022; 10:biomedicines10050972. [PMID: 35625709 PMCID: PMC9139090 DOI: 10.3390/biomedicines10050972] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/20/2022] [Accepted: 04/20/2022] [Indexed: 12/03/2022] Open
Abstract
Testicular germ cell tumors (GCTs) are highly curable malignancies. Excellent survival rates in patients with metastatic disease can be attributed to the exceptional sensitivity of GCTs to cisplatin-based chemotherapy. This hypersensitivity is probably related to alterations in the DNA repair of cisplatin-induced DNA damage, and an excessive apoptotic response. However, chemotherapy fails due to the development of cisplatin resistance in a proportion of patients. The molecular basis of this resistance appears to be multifactorial. Tracking the mechanisms of cisplatin resistance in GCTs, multiple molecules have been identified as potential therapeutic targets. A variety of therapeutic agents have been evaluated in preclinical and clinical studies. These include different chemotherapeutics, targeted therapies, such as tyrosine kinase inhibitors, mTOR inhibitors, PARP inhibitors, CDK inhibitors, and anti-CD30 therapy, as well as immune-checkpoint inhibitors, epigenetic therapy, and others. These therapeutics have been used as single agents or in combination with cisplatin. Some of them have shown promising in vitro activity in overcoming cisplatin resistance, but have not been effective in clinical trials in refractory GCT patients. This review provides a summary of current knowledge about the molecular mechanisms of cisplatin sensitivity and resistance in GCTs and outlines possible therapeutic approaches that seek to overcome this chemoresistance.
Collapse
Affiliation(s)
- Zuzana Országhová
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia; (Z.O.); (M.M.)
| | - Katarina Kalavska
- Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia;
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy Sciences, 845 05 Bratislava, Slovakia
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia; (Z.O.); (M.M.)
- Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia;
| | - Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia; (Z.O.); (M.M.)
- Correspondence:
| |
Collapse
|
|
30
|
Nicu AT, Medar C, Chifiriuc MC, Gradisteanu Pircalabioru G, Burlibasa L. Epigenetics and Testicular Cancer: Bridging the Gap Between Fundamental Biology and Patient Care. Front Cell Dev Biol 2022; 10:861995. [PMID: 35465311 PMCID: PMC9023878 DOI: 10.3389/fcell.2022.861995] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/22/2022] [Indexed: 11/15/2022] Open
Abstract
Testicular cancer is the most common solid tumor affecting young males. Most testicular cancers are testicular germ cell tumors (TGCTs), which are divided into seminomas (SGCTs) and non-seminomatous testicular germ cell tumors (NSGCTs). During their development, primordial germ cells (PGCs) undergo epigenetic modifications and any disturbances in their pattern might lead to cancer development. The present study provides a comprehensive review of the epigenetic mechanisms–DNA methylation, histone post-translational modifications, bivalent marks, non-coding RNA–associated with TGCT susceptibility, initiation, progression and response to chemotherapy. Another important purpose of this review is to highlight the recent investigations regarding the identification and development of epigenetic biomarkers as powerful tools for the diagnostic, prognostic and especially for epigenetic-based therapy.
Collapse
Affiliation(s)
- Alina-Teodora Nicu
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Department of Genetics, University of Bucharest, Bucharest, Romania
| | - Cosmin Medar
- University of Medicine and Pharmacy “Carol Davila”, Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Mariana Carmen Chifiriuc
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Research Institute of University of Bucharest (ICUB), Bucharest, Romania
- Academy of Romanian Scientists, Bucharest, Romania
- Romanian Academy, Bucharest, Romania
| | | | - Liliana Burlibasa
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Department of Genetics, University of Bucharest, Bucharest, Romania
| |
Collapse
|
|
31
|
Seyedabadi N, Shoushtari SY, Soofi A, Arabpour J, Shams Z, Akhavan H, Hosseini-Asl S. Molecular profiles of predictive biomarkers for platinum-based chemotherapy in Non-Small Cell Lung Cancer (NSCLC). Meta Gene 2022. [DOI: 10.1016/j.mgene.2021.100993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
|
|
32
|
Liu S, Qiao W, Sun Q, Luo Y. Chromosome Region Maintenance 1 (XPO1/CRM1) as an Anticancer Target and Discovery of Its Inhibitor. J Med Chem 2021; 64:15534-15548. [PMID: 34669417 DOI: 10.1021/acs.jmedchem.1c01145] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor protein and contributes to cell homeostasis by mediating the transport of cargo from the nucleus to the cytoplasm. CRM1 is a therapeutic target comprised of several tumor types, including osteosarcoma, multiple myeloma, gliomas, and pancreatic cancer. In the past decade, dozens of CRM1 inhibitors have been discovered and developed, including KPT-330, which received FDA approval for multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) in 2019 and 2020, respectively. This review summarizes the biological functions of CRM1, the current understanding of the role CRM1 plays in cancer, the discovery of CRM1 small-molecule inhibitors, preclinical and clinical studies on KPT-330, and other recently developed inhibitors. A new CRM1 inhibition mechanism and structural dynamics are discussed. Through this review, we hope to guide the future design and optimization of CRM1 inhibitors.
Collapse
Affiliation(s)
- Song Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenliang Qiao
- Lung Cancer Center, Laboratory of Lung Cancer, West China Medical School, Sichuan University, Chengdu 610041, China
| | - Qingxiang Sun
- State Key Laboratory of Biotherapy, Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Youfu Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
33
|
Timmerman DM, Eleveld TF, Gillis AJM, Friedrichs CC, Hillenius S, Remmers TL, Sriram S, Looijenga LHJ. The Role of TP53 in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors. Int J Mol Sci 2021; 22:ijms222111774. [PMID: 34769213 PMCID: PMC8583723 DOI: 10.3390/ijms222111774] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/19/2021] [Accepted: 10/26/2021] [Indexed: 12/31/2022] Open
Abstract
Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with TP53 mutations most often localize to the mediastinum. To elucidate the underlying mechanism, TP53 knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type TP53 testicular GCT) and NCCIT cell line (hemizygously mutated TP53, mutant TP53 mediastinal GCT). The full knock-out of TP53 in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that TP53 mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the TP53 mutant and mediastinal GCTs.
Collapse
|
|
34
|
Wang X, Kokabee L, Kokabee M, Conklin DS. Bruton's Tyrosine Kinase and Its Isoforms in Cancer. Front Cell Dev Biol 2021; 9:668996. [PMID: 34307353 PMCID: PMC8297165 DOI: 10.3389/fcell.2021.668996] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 05/25/2021] [Indexed: 01/04/2023] Open
Abstract
Bruton’s tyrosine kinase (BTK) is a soluble tyrosine kinase with central roles in the development, maturation, and signaling of B cells. BTK has been found to regulate cell proliferation, survival, and migration in various B-cell malignancies. Targeting BTK with recently developed BTK inhibitors has been approved by the Food and Drug Administration (FDA) for the treatment of several hematological malignancies and has transformed the treatment of several B-cell malignancies. The roles that BTK plays in B cells have been appreciated for some time. Recent studies have established that BTK is expressed and plays pro-tumorigenic roles in several epithelial cancers. In this review, we focus on novel isoforms of the BTK protein expressed in epithelial cancers. We review recent work on the expression, function, and signaling of these isoforms and their value as potential therapeutic targets in epithelial tumors.
Collapse
Affiliation(s)
- Xianhui Wang
- Department of Biomedical Sciences, Cancer Research Center, State University of New York, Rensselaer, NY, United States
| | - Leila Kokabee
- Department of Biomedical Sciences, Cancer Research Center, State University of New York, Rensselaer, NY, United States
| | - Mostafa Kokabee
- Department of Biomedical Sciences, Cancer Research Center, State University of New York, Rensselaer, NY, United States
| | - Douglas S Conklin
- Department of Biomedical Sciences, Cancer Research Center, State University of New York, Rensselaer, NY, United States
| |
Collapse
|
|
35
|
Muhammad SA, Qousain Naqvi ST, Nguyen T, Wu X, Munir F, Jamshed MB, Zhang Q. Cisplatin's potential for type 2 diabetes repositioning by inhibiting CDKN1A, FAS, and SESN1. Comput Biol Med 2021; 135:104640. [PMID: 34261004 DOI: 10.1016/j.compbiomed.2021.104640] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 12/16/2022]
Abstract
Cisplatin is a DNA-damaging chemotherapeutic agent used for treating cancer. Based on cDNA dataset analysis, we investigated how cisplatin modified gene expression and observed cisplatin-induced dysregulation and system-level variations relating to insulin resistance and type 2 diabetes mellitus (T2DM). T2DM is a multifactorial disease affecting 462 million people in the world, and drug-induced T2DM is a serious issue. To understand this etiology, we designed an integrative, system-level study to identify associations between cisplatin-induced differentially expressed genes (DEGs) and T2DM. From a list of differential expressed genes, cisplatin downregulated the cyclin-dependent kinase inhibitor 1 (CDKN1A), tumor necrosis factor (FAS), and sestrin-1 (SESN1) genes responsible for modifying signaling pathways, including the p53, JAK-STAT, FOXO, MAPK, mTOR, P13-AKT, Toll-like receptor (TLR), adipocytokine, and insulin signaling pathways. These enriched pathways were expressively associated with the disease. We observed significant gene signatures, including SMAD3, IRS, PDK1, PRKAA1, AKT, SOS, RAS, GRB2, MEK1/2, and ERK, interacting with source genes. This study revealed the value of system genetics for identifying the cisplatin-induced genetic variants responsible for the progression of T2DM. Also, by cross-validating gene expression data for T2DM islets, we found that downregulating IRS and PRK families is critical in insulin and T2DM signaling pathways. Cisplatin, by inhibiting CDKN1A, FAS, and SESN1, promotes IRS and PRK activity in a similar way to rosiglitazone (a popular drug used for T2DM treatment). Our integrative, network-based approach can help in understanding the drug-induced pathophysiological mechanisms of diabetes.
Collapse
Affiliation(s)
- Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan.
| | | | - Thanh Nguyen
- Informatics Institute, School of Medicine, The University of Alabama, Birmingham, AL, USA
| | - Xiaogang Wu
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fahad Munir
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Muhammad Babar Jamshed
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - QiYu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| |
Collapse
|
|
36
|
Regan JL, Schumacher D, Staudte S, Steffen A, Lesche R, Toedling J, Jourdan T, Haybaeck J, Mumberg D, Henderson D, Győrffy B, Regenbrecht CRA, Keilholz U, Schäfer R, Lange M. RNA sequencing of long-term label-retaining colon cancer stem cells identifies novel regulators of quiescence. iScience 2021; 24:102618. [PMID: 34142064 PMCID: PMC8185225 DOI: 10.1016/j.isci.2021.102618] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/23/2021] [Accepted: 05/19/2021] [Indexed: 02/07/2023] Open
Abstract
Recent data suggest that therapy-resistant quiescent cancer stem cells (qCSCs) are the source of relapse in colon cancer. Here, using colon cancer patient-derived organoids and xenografts, we identify rare long-term label-retaining qCSCs that can re-enter the cell cycle to generate new tumors. RNA sequencing analyses demonstrated that these cells display the molecular hallmarks of quiescent tissue stem cells, including expression of p53 signaling genes, and are enriched for transcripts common to damage-induced quiescent revival stem cells of the regenerating intestine. In addition, we identify negative regulators of cell cycle, downstream of p53, that we show are indicators of poor prognosis and may be targeted for qCSC abolition in both p53 wild-type and mutant tumors. These data support the temporal inhibition of downstream targets of p53 signaling, in combination with standard-of-care treatments, for the elimination of qCSCs and prevention of relapse in colon cancer.
Colon tumors contain therapy-resistant quiescent cancer stem cells (qCSCs) qCSC gene expression mirrors that of quiescent stem cells of the regenerating gut qCSCs are enriched for p53 signaling genes qCSC elimination may be achieved by inhibiting downstream targets of p53 signaling
Collapse
Affiliation(s)
- Joseph L Regan
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany.,Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Dirk Schumacher
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.,German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
| | - Stephanie Staudte
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany.,German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany.,Department of Radiation Oncology and Radiotherapy, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Andreas Steffen
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Ralf Lesche
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany.,Nuvisan ICB GmbH, 13353 Berlin, Germany
| | - Joern Toedling
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany.,Nuvisan ICB GmbH, 13353 Berlin, Germany
| | - Thibaud Jourdan
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.,Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
| | - Dominik Mumberg
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany
| | - David Henderson
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary.,TTK Cancer Biomarker Research Group, Institute of Enzymology, 1117 Budapest, Hungary
| | - Christian R A Regenbrecht
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.,CELLphenomics GmbH, 13125 Berlin, Germany.,Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Ulrich Keilholz
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Reinhold Schäfer
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.,Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.,German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
| | - Martin Lange
- Bayer AG, Research & Development, Pharmaceuticals, 13342 Berlin, Germany.,Nuvisan ICB GmbH, 13353 Berlin, Germany
| |
Collapse
|
|
37
|
Timmerman DM, Remmers TL, Hillenius S, Looijenga LHJ. Mechanisms of TP53 Pathway Inactivation in Embryonic and Somatic Cells-Relevance for Understanding (Germ Cell) Tumorigenesis. Int J Mol Sci 2021; 22:ijms22105377. [PMID: 34065345 PMCID: PMC8161298 DOI: 10.3390/ijms22105377] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/14/2021] [Accepted: 05/15/2021] [Indexed: 01/10/2023] Open
Abstract
The P53 pathway is the most important cellular pathway to maintain genomic and cellular integrity, both in embryonic and non-embryonic cells. Stress signals induce its activation, initiating autophagy or cell cycle arrest to enable DNA repair. The persistence of these signals causes either senescence or apoptosis. Over 50% of all solid tumors harbor mutations in TP53 that inactivate the pathway. The remaining cancers are suggested to harbor mutations in genes that regulate the P53 pathway such as its inhibitors Mouse Double Minute 2 and 4 (MDM2 and MDM4, respectively). Many reviews have already been dedicated to P53, MDM2, and MDM4, while this review additionally focuses on the other factors that can deregulate P53 signaling. We discuss that P14ARF (ARF) functions as a negative regulator of MDM2, explaining the frequent loss of ARF detected in cancers. The long non-coding RNA Antisense Non-coding RNA in the INK4 Locus (ANRIL) is encoded on the same locus as ARF, inhibiting ARF expression, thus contributing to the process of tumorigenesis. Mutations in tripartite motif (TRIM) proteins deregulate P53 signaling through their ubiquitin ligase activity. Several microRNAs (miRNAs) inactivate the P53 pathway through inhibition of translation. CCCTC-binding factor (CTCF) maintains an open chromatin structure at the TP53 locus, explaining its inactivation of CTCF during tumorigenesis. P21, a downstream effector of P53, has been found to be deregulated in different tumor types. This review provides a comprehensive overview of these factors that are known to deregulate the P53 pathway in both somatic and embryonic cells, as well as their malignant counterparts (i.e., somatic and germ cell tumors). It provides insights into which aspects still need to be unraveled to grasp their contribution to tumorigenesis, putatively leading to novel targets for effective cancer therapies.
Collapse
|
|
38
|
Zhang P, Kitchen-Smith I, Xiong L, Stracquadanio G, Brown K, Richter PH, Wallace MD, Bond E, Sahgal N, Moore S, Nornes S, De Val S, Surakhy M, Sims D, Wang X, Bell DA, Zeron-Medina J, Jiang Y, Ryan AJ, Selfe JL, Shipley J, Kar S, Pharoah PD, Loveday C, Jansen R, Grochola LF, Palles C, Protheroe A, Millar V, Ebner DV, Pagadala M, Blagden SP, Maughan TS, Domingo E, Tomlinson I, Turnbull C, Carter H, Bond GL. Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response. Cancer Res 2021; 81:1667-1680. [PMID: 33558336 PMCID: PMC10266546 DOI: 10.1158/0008-5472.can-20-0177] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 12/25/2020] [Accepted: 02/03/2021] [Indexed: 11/16/2022]
Abstract
Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies. SIGNIFICANCE: These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.
Collapse
Affiliation(s)
- Ping Zhang
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Isaac Kitchen-Smith
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Lingyun Xiong
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Giovanni Stracquadanio
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Katherine Brown
- Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Philipp H Richter
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Marsha D Wallace
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Elisabeth Bond
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Natasha Sahgal
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Samantha Moore
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Svanhild Nornes
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Sarah De Val
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - Mirvat Surakhy
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
| | - David Sims
- Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Xuting Wang
- Environmental Epigenomics and Disease Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences-National Institutes of Health, Research Triangle Park, North Carolina
| | - Douglas A Bell
- Environmental Epigenomics and Disease Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences-National Institutes of Health, Research Triangle Park, North Carolina
| | - Jorge Zeron-Medina
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
| | - Yanyan Jiang
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, Oxford, United Kingdom
| | - Anderson J Ryan
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, Oxford, United Kingdom
| | - Joanna L Selfe
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
| | - Janet Shipley
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
| | - Siddhartha Kar
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Paul D Pharoah
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Chey Loveday
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
| | - Rick Jansen
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, the Netherlands
| | | | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Andrew Protheroe
- Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Val Millar
- Target Discovery Institute, University of Oxford, Nuffield Department of Medicine, Oxford, United Kingdom
| | - Daniel V Ebner
- Target Discovery Institute, University of Oxford, Nuffield Department of Medicine, Oxford, United Kingdom
| | - Meghana Pagadala
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Sarah P Blagden
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Timothy S Maughan
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Enric Domingo
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Ian Tomlinson
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Clare Turnbull
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
| | - Hannah Carter
- Department of Medicine, University of California, San Diego, La Jolla, California.
| | - Gareth L Bond
- Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom.
| |
Collapse
|
|
39
|
Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors. Cancers (Basel) 2021; 13:cancers13071506. [PMID: 33805941 PMCID: PMC8036638 DOI: 10.3390/cancers13071506] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/16/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary This minireview focuses on the role of epigenetics in testicular cancer. A working model is developed that postulates that epigenetic features that drive testicular cancer malignancy also enable these tumors to be cured at a high rate with chemotherapy. Chemoresistance may occur by epigenetic uncoupling of malignancy and chemosensitivity, a scenario that may be amenable to epigenetic-based therapies. Abstract Compared to many common solid tumors, the main genetic drivers of most testicular germ cell tumors (TGCTs) are unknown. Decades of focus on genomic alterations in TGCTs including awareness of a near universal increase in copies of chromosome 12p have failed to uncover exceptional driver genes, especially in genes that can be targeted therapeutically. Thus far, TGCT patients have missed out on the benefits of targeted therapies available to treat most other malignancies. In the past decade there has been a greater appreciation that epigenetics may play an especially prominent role in TGCT etiology, progression, and hypersensitivity to conventional chemotherapy. While genetics undoubtedly plays a role in TGCT biology, this mini-review will focus on the epigenetic “states” or features of testicular cancer, with an emphasis on DNA methylation, histone modifications, and miRNAs associated with TGCT susceptibility, initiation, progression, and response to chemotherapy. In addition, we comment on the current status of epigenetic-based therapy and epigenetic biomarker development for TGCTs. Finally, we suggest a unifying “rock and a hard place” or “differentiate or die” model where the tumorigenicity and curability of TGCTs are both dependent on common but still ill-defined epigenetic states.
Collapse
|
|
40
|
Torres-Martinez Z, Delgado Y, Ferrer-Acosta Y, Suarez-Arroyo IJ, Joaquín-Ovalle FM, Delinois LJ, Griebenow K. Key genes and drug delivery systems to improve the efficiency of chemotherapy. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:163-191. [PMID: 34142021 PMCID: PMC8208690 DOI: 10.20517/cdr.2020.64] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer cells can develop resistance to anticancer drugs, thereby becoming tolerant to treatment through different mechanisms. The biological mechanisms leading to the generation of anticancer treatment resistance include alterations in transmembrane proteins, DNA damage and repair mechanisms, alterations in target molecules, and genetic responses, among others. The most common anti-cancer drugs reported to develop resistance to cancer cells include cisplatin, doxorubicin, paclitaxel, and fluorouracil. These anticancer drugs have different mechanisms of action, and specific cancer types can be affected by different genes. The development of drug resistance is a cellular response which uses differential gene expression, to enable adaptation and survival of the cell to diverse threatening environmental agents. In this review, we briefly look at the key regulatory genes, their expression, as well as the responses and regulation of cancer cells when exposed to anticancer drugs, along with the incorporation of alternative nanocarriers as treatments to overcome anticancer drug resistance.
Collapse
Affiliation(s)
- Zally Torres-Martinez
- Chemistry Department, University of Puerto Rico- Rio Piedras campus, San Juan, PR 00936, USA
| | - Yamixa Delgado
- Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00726, USA
| | - Yancy Ferrer-Acosta
- Neuroscience Department, Universidad Central del Caribe, Bayamon, PR 00956, USA
| | | | - Freisa M Joaquín-Ovalle
- Chemistry Department, University of Puerto Rico- Rio Piedras campus, San Juan, PR 00936, USA
| | - Louis J Delinois
- Chemistry Department, University of Puerto Rico- Rio Piedras campus, San Juan, PR 00936, USA
| | - Kai Griebenow
- Chemistry Department, University of Puerto Rico- Rio Piedras campus, San Juan, PR 00936, USA
| |
Collapse
|
|
41
|
Yang G, Guan W, Cao Z, Guo W, Xiong G, Zhao F, Feng M, Qiu J, Liu Y, Zhang MQ, You L, Zhang T, Zhao Y, Gu J. Integrative Genomic Analysis of Gemcitabine Resistance in Pancreatic Cancer by Patient-derived Xenograft Models. Clin Cancer Res 2021; 27:3383-3396. [PMID: 33674273 DOI: 10.1158/1078-0432.ccr-19-3975] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 12/21/2020] [Accepted: 03/02/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Gemcitabine is most commonly used for pancreatic cancer. However, the molecular features and mechanisms of the frequently occurring resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment. EXPERIMENTAL DESIGN In this study, we established 66 patient-derived xenografts (PDXs) on the basis of clinical pancreatic cancer specimens and treated them with gemcitabine. We generated multiomics data (including whole-exome sequencing, RNA sequencing, miRNA sequencing, and DNA methylation array) of 15 drug-sensitive and 13 -resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and acquired resistance. Then, short hairpin RNA-based high-content screening was implemented to validate the function of the deregulated genes. RESULTS The comprehensive multiomics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in pancreatic cancer cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of patients with pancreatic cancer and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, and hypoxia-inducible factor-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance. CONCLUSIONS This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provides potential therapy targets for overcoming gemcitabine resistance.
Collapse
Affiliation(s)
- Gang Yang
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Wenfang Guan
- MOE Key Laboratory of Bioinformatics, Division of BNRist Bioinformatics, Department of Automation, Tsinghua University, Beijing, P.R. China
| | - Zhe Cao
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Wenbo Guo
- MOE Key Laboratory of Bioinformatics, Division of BNRist Bioinformatics, Department of Automation, Tsinghua University, Beijing, P.R. China
| | - Guangbing Xiong
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Fangyu Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Mengyu Feng
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Jiangdong Qiu
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Yueze Liu
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Michael Q Zhang
- MOE Key Laboratory of Bioinformatics, Division of BNRist Bioinformatics, Department of Automation, Tsinghua University, Beijing, P.R. China
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, P.R. China
- Department of Biological Sciences, Center for Systems Biology, the University of Texas at Dallas, Richardson, Texas
| | - Lei You
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
| | - Taiping Zhang
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
| | - Yupei Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and, Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
| | - Jin Gu
- MOE Key Laboratory of Bioinformatics, Division of BNRist Bioinformatics, Department of Automation, Tsinghua University, Beijing, P.R. China.
| |
Collapse
|
|
42
|
Animireddy S, Kavadipula P, Kotapalli V, Gowrishankar S, Rao S, Bashyam MD. Aberrant cytoplasmic localization of ARID1B activates ERK signaling and promotes oncogenesis. J Cell Sci 2021; 134:jcs251637. [PMID: 33443092 DOI: 10.1242/jcs.251637] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
The ARID1B (BAF250b) subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. We employed in silico prediction, intracellular fluorescence and cellular fractionation-based subcellular localization analyses to identify the ARID1B nuclear localization signal (NLS). A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised in its canonical transcription activation and tumor suppressive functions, as expected. Surprisingly however, cytoplasmic localization appeared to induce a gain of oncogenic function for ARID1B, as evidenced from several cell line- and mouse xenograft-based assays. Mechanistically, cytoplasm-localized ARID1B could bind c-RAF (RAF1) and PPP1CA causing stimulation of RAF-ERK signaling and β-catenin (CTNNB1) transcription activity. ARID1B harboring NLS mutations derived from tumor samples also exhibited aberrant cytoplasmic localization and acquired a neo-morphic oncogenic function via activation of RAF-ERK signaling. Furthermore, immunohistochemistry on a tissue microarray revealed significant correlation of ARID1B cytoplasmic localization with increased levels of active forms of ERK1 and ERK2 (also known as MAPK3 and MAPK1) and of β-catenin, as well as with advanced tumor stage and lymph node positivity in human primary pancreatic tumor tissues. ARID1B therefore promotes oncogenesis through cytoplasm-based gain-of-function mechanisms in addition to dysregulation in the nucleus.This article has an associated First Person interview with the first author of the paper.
Collapse
Affiliation(s)
- Srinivas Animireddy
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India
- Graduate Studies, Manipal Academy of Higher Education, Manipal 576104, India
| | - Padmavathi Kavadipula
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India
| | - Viswakalyan Kotapalli
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India
| | | | - Satish Rao
- Krishna Institute of Medical Sciences, Hyderabad 500003, India
| | - Murali Dharan Bashyam
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India
| |
Collapse
|
|
43
|
Mechanisms of Cisplatin in Combination with Repurposed Drugs against Human Endometrial Carcinoma Cells. Life (Basel) 2021; 11:life11020160. [PMID: 33669781 PMCID: PMC7922822 DOI: 10.3390/life11020160] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/10/2021] [Accepted: 02/16/2021] [Indexed: 12/18/2022] Open
Abstract
Although endometrial carcinoma is one of the most common gynecological malignancies worldwide, its precise etiology remains unknown. Moreover, no novel adjuvant and/or targeted therapies are currently being developed to achieve greater efficacy for endometrial cancer patients who develop chemotherapeutic drug resistance. In this study, we used three human endometrial cancer cell lines, RL95-2, HEC-1-A, and KLE, to investigate the responsiveness of cisplatin alone and in combination with potential repurposed drugs. We first found that RL95-2 cells were more sensitive to cisplatin than HEC-1-A or KLE cells. The cytotoxicity of cisplatin in RL95-2 cells may reflect its ability to perturb the cell cycle, reactive oxygen species production and autophagy as well as to induce senescence and DNA damage. Similar effects, although not DNA damage, were also observed in HEC-1-A and KLE cells. In addition, downregulation of p53 and/or cyclin D1 may also impact the responsiveness of HEC-1-A and KLE cells to cisplatin. We also observed that resveratrol, trichostatin A (TSA), caffeine, or digoxin increased the apoptotic process of cisplatin toward RL95-2 cells, while amiodarone or TSA increased its apoptotic process toward HEC-1-A cells. The combination index supported the assertion that the combination of cisplatin with caffeine, amiodarone, resveratrol, metformin, digoxin, or TSA increases the cytotoxicity of cisplatin in HEC-1-A cells. These findings suggest potential strategies for enhancing the efficacy of cisplatin to overcome drug resistance in endometrial carcinoma patients.
Collapse
|
|
44
|
Bharti D, Tikka M, Lee SY, Bok EY, Lee HJ, Rho GJ. Female Germ Cell Development, Functioning and Associated Adversities under Unfavorable Circumstances. Int J Mol Sci 2021; 22:1979. [PMID: 33671303 PMCID: PMC7922109 DOI: 10.3390/ijms22041979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 01/07/2023] Open
Abstract
In the present era, infertility is one of the major issues which restricts many couples to have their own children. Infertility is the inability to achieve a clinical pregnancy after regular unprotected sexual intercourse for the period of one year or more. Various factors including defective male or female germ cell development, unhealthy and improper lifestyles, diseases like cancer and associated chemo-or-radiation therapies, congenital disorders, etc., may be responsible for infertility. Therefore, it is highly important to understand the basic concepts of germ cell development including primordial germ cell (PGC) formation, specification, migration, entry to genital ridges and their molecular mechanisms, activated pathways, paracrine and autocrine signaling, along with possible alteration which can hamper germ cell development and can cause adversities like cancer progression and infertility. Knowing all these aspects in a proper way can be very much helpful in improving our understanding about gametogenesis and finding possible ways to cure related disorders. Here in this review, various aspects of gametogenesis especially female gametes and relevant factors causing functional impairment have been thoroughly discussed.
Collapse
Affiliation(s)
- Dinesh Bharti
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea; (D.B.); (S.-Y.L.); (E.-Y.B.)
| | - Manisha Tikka
- Department of Zoology and Environmental Sciences, Punjabi University, Patiala 147002, India;
| | - Sang-Yun Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea; (D.B.); (S.-Y.L.); (E.-Y.B.)
| | - Eun-Yeong Bok
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea; (D.B.); (S.-Y.L.); (E.-Y.B.)
| | - Hyeon-Jeong Lee
- Department of Medicine, University of California, San Diego, CA 92093-0021, USA;
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea; (D.B.); (S.-Y.L.); (E.-Y.B.)
| |
Collapse
|
|
45
|
Kuang Y, Kang J, Li H, Liu B, Zhao X, Li L, Jin X, Li Q. Multiple functions of p21 in cancer radiotherapy. J Cancer Res Clin Oncol 2021; 147:987-1006. [PMID: 33547489 DOI: 10.1007/s00432-021-03529-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Greater than half of cancer patients experience radiation therapy, for both radical and palliative objectives. It is well known that researches on radiation response mechanisms are conducive to improve the efficacy of cancer radiotherapy. p21 was initially identified as a widespread inhibitor of cyclin-dependent kinases, transcriptionally modulated by p53 and a marker of cellular senescence. It was once considered that p21 acts as a tumour suppressor mainly to restrain cell cycle progression, thereby resulting in growth suppression. With the deepening researches on p21, p21 has been found to regulate radiation responses via participating in multiple cellular processes, including cell cycle arrest, apoptosis, DNA repair, senescence and autophagy. Hence, a comprehensive summary of the p21's functions in radiation response will provide a new perspective for radiotherapy against cancer. METHODS We summarize the recent pertinent literature from various electronic databases, including PubMed and analyzed several datasets from Gene Expression Omnibus database. This review discusses how p21 influences the effect of cancer radiotherapy via involving in multiple signaling pathways and expounds the feasibility, barrier and risks of using p21 as a biomarker as well as a therapeutic target of radiotherapy. CONCLUSION p21's complicated and important functions in cancer radiotherapy make it a promising therapeutic target. Besides, more thorough insights of p21 are needed to make it a safe therapeutic target.
Collapse
Affiliation(s)
- Yanbei Kuang
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jian Kang
- College of Energy and Power Engineering, Lanzhou University of Technology, Lanzhou, 730050, China
| | - Hongbin Li
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, 730050, China
| | - Bingtao Liu
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xueshan Zhao
- The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Linying Li
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaodong Jin
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Qiang Li
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| |
Collapse
|
|
46
|
Hodeify R, Siddiqui SS, Matar R, Vazhappilly CG, Merheb M, Al Zouabi H, Marton J. Modulation of calcium-binding proteins expression and cisplatin chemosensitivity by calcium chelation in human breast cancer MCF-7 cells. Heliyon 2021; 7:e06041. [PMID: 33532651 PMCID: PMC7829211 DOI: 10.1016/j.heliyon.2021.e06041] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/21/2020] [Accepted: 01/15/2021] [Indexed: 11/22/2022] Open
Abstract
Cisplatin (CDDP) is currently one of the most effective FDA-approved treatments for breast cancer. Previous studies have shown that CDDP-induced cell death in human breast cancer (MCF-7) cells is associated with disruption of calcium homeostasis. However, whether the sensitivity of breast cancer cells to cisplatin is associated with dysregulation of the expression of calcium-binding proteins (CaBPs) remains unknown. In this study, we evaluated the effect of the intracellular calcium chelator (BAPTA-AM) on viability of MCF-7 cells in the presence of toxic and sub-toxic doses of cisplatin. Furthermore, this study assessed the expression of CaBPs, calmodulin, S100A8, and S100A14 in MCF-7 cells treated with cisplatin. Cell viability was determined using MTT-based in vitro toxicity assay. Intracellular calcium imaging was done using Fluo-4 AM, a cell-permeant fluorescent calcium indicator. Expression of CaBPs was tested using real-time quantitative PCR. Exposure of cells to increasing amounts of CDDP correlated with increasing fluorescence of the intracellular calcium indicator, Fluo-4 AM. Conversely, treating cells with cisplatin significantly decreased mRNA levels of calmodulin, S100A8, and S100A14. Treatment of the cells with calcium chelator, BAPTA-AM, significantly enhanced the cytotoxic effects of sub-toxic dose of cisplatin. Our results indicated a statistically significant negative correlation between calmodulin, S100A8, and S100A14 expression and sensitivity of breast cancer cells to a sub-toxic dose of cisplatin. We propose that modulating the activity of calcium-binding proteins, calmodulin, S100A8, and S100A14, could be used to increase cisplatin efficacy, lowering its treatment dosage while maintaining its chemotherapeutic value.
Collapse
Affiliation(s)
- Rawad Hodeify
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates
| | - Shoib Sarwar Siddiqui
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates
| | - Rachel Matar
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates
| | - Cijo George Vazhappilly
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates
| | - Maxime Merheb
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates
| | - Hussain Al Zouabi
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates
| | - John Marton
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates
| |
Collapse
|
|
47
|
Krishnan R, Murugiah M, Lakshmi, NP, Mahalingam S. Guanine nucleotide binding protein like-1 (GNL1) promotes cancer cell proliferation and survival through AKT/p21 CIP1 signaling cascade. Mol Biol Cell 2020; 31:2904-2919. [PMID: 33147101 PMCID: PMC7927199 DOI: 10.1091/mbc.e20-04-0267] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 10/14/2020] [Accepted: 10/27/2020] [Indexed: 12/03/2022] Open
Abstract
Human guanine nucleotide binding protein like 1 (GNL1) is an evolutionary conserved putative nucleolar GTPase belonging to the HSR1_MMR1 subfamily of GTPases. GNL1 was found to be highly up-regulated in various cancers. Here, we report for the first time that GNL1 inhibits apoptosis by modulating the expression of Bcl2 family of proteins and the cleavage of caspases 7 and 8. Furthermore, GNL1 protects colon cancer cells from chemo-drug-induced apoptosis. Interestingly, GNL1 up-regulates the expression of p53 and its transcriptional target, p21 but the up-regulation of p21 was found to be p53 dependent as well as independent mechanisms. Our results further demonstrate that GNL1 promotes cell growth and survival by inducing cytoplasmic retention and stabilization of p21 through AKT-mediated phosphorylation. In addition, GNL1 failed to inhibit apoptosis under p21 knockdown conditions which suggests the critical role of p21 in GNL1-mediated cell survival. Finally, an inverse correlation of GNL1, p21, and AKT expression in primary colon and breast cancer with patient survival suggests their critical role in tumorigenesis. Collectively, our study reveals that GNL1 executes its antiapoptotic function by a novel mechanism and suggests that it may function as a regulatory component of the PI3K/AKT/p21 signaling network to promote cell proliferation and survival in cancers.
Collapse
Affiliation(s)
- Rehna Krishnan
- Laboratory of Molecular Cell Biology, National Cancer Tissue Biobank, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology-Madras, Chennai 600 036, India
| | - Mariappan Murugiah
- Laboratory of Molecular Cell Biology, National Cancer Tissue Biobank, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology-Madras, Chennai 600 036, India
| | - Naga Padma Lakshmi,
- Laboratory of Molecular Cell Biology, National Cancer Tissue Biobank, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology-Madras, Chennai 600 036, India
| | - Sundarasamy Mahalingam
- Laboratory of Molecular Cell Biology, National Cancer Tissue Biobank, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology-Madras, Chennai 600 036, India
| |
Collapse
|
|
48
|
Lin J, Fan X, Chen J, Xie X, Yu H. Small interfering RNA-mediated knockdown of KRT80 suppresses colorectal cancer proliferation. Exp Ther Med 2020; 20:176. [PMID: 33101466 PMCID: PMC7579811 DOI: 10.3892/etm.2020.9306] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 04/17/2020] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world and its development is associated with oncogenic dysfunction. Therefore, the present study aimed to identify differentially expressed genes (DEGs) in CRC tissues and to determine the role of keratin 80 (KRT80) in CRC cell proliferation. DEGs were initially screened in 32 paired CRC tissues and matched adjacent normal tissues from RNA-Seq datasets in The Cancer Genome Atlas database using the limma package in R software. In total, 2,114 DEGs were identified, of which KRT80 was discovered to be the most upregulated in CRC tissues. Moreover, increased KRT80 expression levels were confirmed in tissues collected from 50 patients with CRC using reverse transcription-quantitative PCR, and its increased expression levels were significantly associated with increased lymph node and distant metastasis and a higher pathological stage. Furthermore, KRT80 knockdown using siRNA decreased the viability and proliferation of CRC cells. Finally, pathway analysis revealed that the proteins co-expressed with KRT80 in CRC were enriched in the cell cycle, DNA replication, immune system, metabolism of protein and RNA, signal transduction and other cellular processes. Among them, the cell cycle and DNA replication pathways contained the highest number of the proteins identified. In conclusion, the findings of the present study suggested that KRT80 may be overexpressed in CRC tissues. Furthermore, KRT80 may be involved in the proliferation of CRC cells, which is likely through its ability to regulate the cell cycle and DNA replication pathways, thus it may serve as a potential therapeutic target for patients with CRC.
Collapse
Affiliation(s)
- Jiatian Lin
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Xiaoqin Fan
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Junhui Chen
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Xina Xie
- Guangdong Key Laboratory of Systems and Synthetic Biology for Urogenital Tumors, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Hongjian Yu
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Correspondence to: Dr Hongjian Yu, Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, Guangdong 518036, P.R. China
| |
Collapse
|
|
49
|
Kozakova K, Mego M, Cheng L, Chovanec M. Promising novel therapies for relapsed and refractory testicular germ cell tumors. Expert Rev Anticancer Ther 2020; 21:53-69. [PMID: 33138660 DOI: 10.1080/14737140.2021.1838279] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Germ cell tumors (GCTs) are the most common solid malignancies in young men. The overall cure rate of GCT patients in metastatic stage is excellent, however; patients with relapsed or refractory disease have poor prognosis. Attempts to treat refractory disease with novel effective treatment to improve prognosis have been historically dismal and the ability to predict prognosis and treatment response in GCTs did not sufficiently improve in the last three decades. AREAS COVERED We performed a comprehensive literature search of PubMed/MEDLINE to identify original and review articles (years 1964-2020) reporting on current improvement salvage treatment in GCTs and novel treatment options including molecularly targeted therapy and epigenetic approach. Review articles were further searched for additional original articles. EXPERT OPINION Despite multimodal treatment approaches the treatment of relapsed or platinum-refractory GCTs remains a challenge. High-dose chemotherapy (HDCT) regimens with autologous stem-cell transplant (ASCT) from peripheral blood showed promising results in larger retrospective studies. Promising results from in vitro studies raised high expectations in molecular targets. So far, the lacking efficacy in small and unselected trials do not shed a light on targeted therapy. Currently, wide inclusion of patients into clinical trials is highly advised.
Collapse
Affiliation(s)
- Kristyna Kozakova
- Department of Anesthesiology and Intensive Care Medicine, National Cancer Institute , Bratislava, Slovakia.,2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute , Bratislava, Slovakia
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute , Bratislava, Slovakia.,Division of Hematology Oncology, Indiana University Simon Cancer Center , Indianapolis, IN, USA
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine , Indianapolis, IN, USA.,Department of Urology, Indiana University School of Medicine , Indianapolis, IN, USA
| | - Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute , Bratislava, Slovakia.,Division of Hematology Oncology, Indiana University Simon Cancer Center , Indianapolis, IN, USA
| |
Collapse
|
|
50
|
ATM inhibition overcomes resistance to histone deacetylase inhibitor due to p21 induction and cell cycle arrest. Oncotarget 2020; 11:3432-3442. [PMID: 32973968 PMCID: PMC7500109 DOI: 10.18632/oncotarget.27723] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 06/20/2020] [Indexed: 12/05/2022] Open
Abstract
The antiproliferative effect induced by histone deactylase inhibitors (HDACi) is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug. The direct targeting of p21 is not feasible. An alternate approach could selectively target factors upstream or downstream of p21 that affect one or more specific aspects of p21 function. HDAC inhibitors appear to activate p21 expression via ataxia telangiectasia mutated (ATM) activity. KU60019, a specific ATM inhibitor, has shown to decrease the p21 protein levels in a concentration dependent manner. We explored the potential synergistic interaction of the ATM inhibitor with romidepsin, given the potential complementary impact around p21. A synergistic cytotoxic effect was observed in all lymphoma cell lines examined when the HDACi was combined with KU60019. The increase in apoptosis correlates with decreased expression of p21 due to the ATM inhibitor. KU60019 decreased expression of the cyclin-dependent kinase inhibitor at the transcriptional level, compromising the ability of HDACi to induce p21 and cell cycle arrest and ultimately facilitating a shift toward the apoptotic phase. Central to the increased apoptosis observed when romidepsin is combined with KU60019 is the reduced expression of p21 and the absence of a G2/M cell cycle arrest that would be exploited by the tumor cells to evade the cytotoxic effect of the HDAC inhibitor. We believe this strategy may offer a promising way to identify rational combinations for HDACi directed therapy, improving their activity in malignant disease.
Collapse
|