|
1
|
Song Y, Weng W, Wu S. Investigating the Potential Effects of 6PPDQ on Prostate Cancer Through Network Toxicology and Molecular Docking. TOXICS 2024; 12:891. [PMID: 39771106 PMCID: PMC11728691 DOI: 10.3390/toxics12120891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/25/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025]
Abstract
(1) Background: N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPDQ), as a newly discovered environmental toxin, has been found more frequently in our living conditions. The literature reports that damage to the reproductive and cardiovascular system is associated with exposure to 6PPDQ. However, the relationship between 6PPDQ and cancer still requires more investigation. This research aims to investigate the association between 6PPDQ and prostate cancer. (2) Methods and Results: Based on the data retrieved from the Pharmmapper, CTD, SEA, SwissTargetPrediction, GeneCard, and OMIM databases, we summarized 239 potential targets utilizing the Venn tool. Through the STRING network database and Cytoscape software, we constructed a PPI network and confirmed ten core targets, including IGF1R, PIK3R1, PTPN11, EGFR, SRC, GRB2, JAK2, SOS1, KDR, and IRS1. We identified the potential pathways through which 6PPDQ acts on these core targets using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Ultimately, through molecular docking methods, 6PPDQ binds closely with these ten core targets. These findings indicate that 6PPDQ may influence the proteins related to prostate cancer and may be linked to prostate cancer via several known signaling pathways. (3) Conclusions: This article employs innovative network toxicology to elucidate the prostate carcinogenic effects of 6PPDQ through its modulation of specific vital genes and signaling pathways, thereby establishing a foundational platform for future investigations into the impact of 6PPDQ on prostate cancer and potentially other tumors.
Collapse
Affiliation(s)
- Yuanzhi Song
- Department of Urology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China;
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing 400014, China
- Chongqing Key Laboratory of Structural BirthDefect and Reconstruction, Chongqing 400014, China
| | - Wuhong Weng
- The First Clinic College, Chongqing Medical University, Chongqing 401331, China;
| | - Shengde Wu
- Department of Urology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China;
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing 400014, China
- Chongqing Key Laboratory of Structural BirthDefect and Reconstruction, Chongqing 400014, China
| |
Collapse
|
|
2
|
Hassan D, Menges CW, Testa JR, Bellacosa A. AKT kinases as therapeutic targets. J Exp Clin Cancer Res 2024; 43:313. [PMID: 39614261 PMCID: PMC11606119 DOI: 10.1186/s13046-024-03207-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/03/2024] [Indexed: 12/01/2024] Open
Abstract
AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs.
Collapse
Affiliation(s)
- Dalal Hassan
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
- Thomas Jefferson University, 901 Walnut St, Philadelphia, PA, 19107, USA
| | - Craig W Menges
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Alfonso Bellacosa
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
| |
Collapse
|
|
3
|
Barker RM, Chambers A, Kehoe PG, Rowe E, Perks CM. Untangling the role of tau in sex hormone responsive cancers: lessons learnt from Alzheimer's disease. Clin Sci (Lond) 2024; 138:1357-1369. [PMID: 39469929 PMCID: PMC11522895 DOI: 10.1042/cs20230317] [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: 05/22/2024] [Revised: 09/20/2024] [Accepted: 10/02/2024] [Indexed: 10/30/2024]
Abstract
Tubulin associated unit has been extensively studied in neurodegenerative diseases including Alzheimer's disease (AD), whereby its hyperphosphorylation and accumulation contributes to disease pathogenesis. Tau is abundantly expressed in the central nervous system but is also present in non-neuronal tissues and in tumours including sex hormone responsive cancers such as breast and prostate. Curiously, hormonal effects on tau also exist in an AD context from numerous studies on menopause, hormone replacement therapy, and androgen deprivation therapy. Despite sharing some risk factors, most importantly advancing age, there are numerous reports from population studies of, currently poorly explained inverse associations between cancer and Alzheimer's disease. We previously reviewed important components of the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signalling pathway and their differential modulation in relation to the two diseases. Similarly, receptor tyrosine kinases, estrogen receptor and androgen receptor have all been implicated in the pathogenesis of both cancer and AD. In this review, we focus on tau and its effects in hormone responsive cancer in terms of development, progression, and treatment and in relation to sex hormones and PI3K/Akt signalling molecules including IRS-1, PTEN, Pin1, and p53.
Collapse
Affiliation(s)
- Rachel M. Barker
- Cancer Endocrinology Group, Learning & Research Building, Southmead Hospital, Translational Health Sciences, Bristol Medical School, Bristol BS10 5NB, UK
| | - Alfie Chambers
- Cancer Endocrinology Group, Learning & Research Building, Southmead Hospital, Translational Health Sciences, Bristol Medical School, Bristol BS10 5NB, UK
| | - Patrick G. Kehoe
- Department of Urology, Bristol Urological Institute, Southmead Hospital, Bristol BS10 5NB, UK
| | - Edward Rowe
- Dementia Research Group, Learning & Research Building, Southmead Hospital, Translational Health Sciences, Bristol Medical School, Bristol BS10 5NB, UK
| | - Claire M. Perks
- Cancer Endocrinology Group, Learning & Research Building, Southmead Hospital, Translational Health Sciences, Bristol Medical School, Bristol BS10 5NB, UK
| |
Collapse
|
|
4
|
Ishiguro N, Nakagawa M. ASPSCR1::TFE3-mediated upregulation of insulin receptor substrate 2 (IRS-2) activates PI3K/AKT signaling and promotes malignant phenotype. Int J Biochem Cell Biol 2024; 176:106676. [PMID: 39419345 DOI: 10.1016/j.biocel.2024.106676] [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: 05/24/2024] [Revised: 10/10/2024] [Accepted: 10/12/2024] [Indexed: 10/19/2024]
Abstract
The ASPSCR1::TFE3 fusion gene, resulting from chromosomal translocation, is detected in alveolar soft part sarcoma (ASPS) and a subset of renal cell carcinomas (RCC). The ASPSCR1::TFE3 oncoprotein, functioning as an aberrant transcription factor, contributes to tumor development and progression by inappropriately upregulating target genes. Here, we identified insulin receptor substrate 2 (IRS-2), a cytoplasmic adaptor protein, as a novel transcriptional target of ASPSCR1::TFE3. Ectopic expression of ASPSCR1::TFE3 led to increased IRS-2 mRNA and protein levels. Chromatin immunoprecipitation and luciferase assays demonstrated that ASPSCR1::TFE3 bound to the IRS-2 promoter region and enhanced its transcription. Moreover, IRS-2 was highly expressed in the ASPSCR1::TFE3-positive RCC cell line FU-UR1, while small interfering RNA-mediated depletion of ASPSCR1::TFE3 markedly decreased IRS-2 mRNA and protein levels. Functionally, IRS-2 knockdown attenuated activation of the PI3K/AKT pathway and reduced proliferation, migration, invasion, adhesion, and clonogenicity in FU-UR1 cells. Pharmacological inhibition of IRS-2 also reduced AKT activation as well as cell viability, clonogenicity, migration, invasion, and adhesion. These findings suggest that IRS-2, regulated by ASPSCR1::TFE3, promotes tumor progression by activating PI3K/AKT signaling and enhancing the malignant phenotype.
Collapse
MESH Headings
- Humans
- Insulin Receptor Substrate Proteins/metabolism
- Insulin Receptor Substrate Proteins/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Proto-Oncogene Proteins c-akt/genetics
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
- Signal Transduction
- Phosphatidylinositol 3-Kinases/metabolism
- Phosphatidylinositol 3-Kinases/genetics
- Cell Line, Tumor
- Up-Regulation
- Gene Expression Regulation, Neoplastic
- Cell Movement/genetics
- Cell Proliferation
- Phenotype
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/metabolism
- Kidney Neoplasms/pathology
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Sarcoma, Alveolar Soft Part/pathology
- Sarcoma, Alveolar Soft Part/genetics
- Sarcoma, Alveolar Soft Part/metabolism
- Intracellular Signaling Peptides and Proteins
Collapse
Affiliation(s)
- Naoko Ishiguro
- Department of Pathobiological Science and Technology, Faculty of Medicine, Tottori University, Yonago, Japan.
| | - Mayumi Nakagawa
- Department of Pathobiological Science and Technology, Faculty of Medicine, Tottori University, Yonago, Japan
| |
Collapse
|
|
5
|
Zhang SY, Luo Q, Xiao LR, Yang F, Zhu J, Chen XQ, Yang S. Role and mechanism of NCAPD3 in promoting malignant behaviors in gastric cancer. Front Pharmacol 2024; 15:1341039. [PMID: 38711992 PMCID: PMC11070777 DOI: 10.3389/fphar.2024.1341039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 03/30/2024] [Indexed: 05/08/2024] Open
Abstract
Background Gastric cancer (GC) is one of the major malignancies threatening human lives and health. Non-SMC condensin II complex subunit D3 (NCAPD3) plays a crucial role in the occurrence of many diseases. However, its role in GC remains unexplored. Materials and Methods The Cancer Genome Atlas (TCGA) database, clinical samples, and cell lines were used to analyze NCAPD3 expression in GC. NCAPD3 was overexpressed and inhibited by lentiviral vectors and the CRISPR/Cas9 system, respectively. The biological functions of NCAPD3 were investigated in vitro and in vivo. Gene microarray, Gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to establish the potential mechanisms. Results NCAPD3 was highly expressed in GC and was associated with a poor prognosis. NCAPD3 upregulation significantly promoted the malignant biological behaviors of gastric cancer cell, while NCAPD3 inhibition exerted a opposite effect. NCAPD3 loss can directly inhibit CCND1 and ESR1 expression to downregulate the expression of downstream targets CDK6 and IRS1 and inhibit the proliferation of gastric cancer cells. Moreover, NCAPD3 loss activates IRF7 and DDIT3 to regulate apoptosis in gastric cancer cells. Conclusion Our study revealed that NCAPD3 silencing attenuates malignant phenotypes of GC and that it is a potential target for GC treatment.
Collapse
Affiliation(s)
- Su-Yun Zhang
- Departments of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Qiong Luo
- Departments of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Li-Rong Xiao
- Departments of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Fan Yang
- Departments of Respiratory and Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Jian Zhu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiang-Qi Chen
- Departments of Respiratory and Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Fuzhou, Fujian, China
| | - Sheng Yang
- Departments of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Fuzhou, Fujian, China
| |
Collapse
|
|
6
|
Singh RK, Chaurasiya AK, Kumar A. Ab initio modeling of human IRS1 protein to find novel target to dock with drug MH to mitigate T2DM diabetes by insulin signaling. 3 Biotech 2024; 14:108. [PMID: 38476643 PMCID: PMC10925585 DOI: 10.1007/s13205-024-03955-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 02/03/2024] [Indexed: 03/14/2024] Open
Abstract
IRS1 is a cytoplasmic adaptor protein that helps in cellular growth, glucose metabolism, proliferation, and differentiation. Highly disordered (insulin receptor substrate 1) IRS1 protein sequence (mol.wt- 131,590.97 da) has been used to develop model using ab initio modeling technique by I-Tassar tool and Discovery Studio/ DogSite Server to decipher a novel active site. The constructed protein model has been submitted with PMDB Id- PM0082210. GRAVY index of IRS1 model ( - 0.675) indicated surface protein-water interaction. Protparam tool instability index (75.22) demonstrated disorderedness combined with loops owing to prolines/glycines. After refinement, the Ramachandran plot showed that 88 percent of AAs were present in the allowed region and only 0.5% in the disallowed region. Novel IRS1 model protein has 10 α-helices, 22 β-sheets, 20 β-hairpins, 5 β-bulges, 47 strands, 105 β-turns, and 8 γ-turns. Docking of IRS1 with drug MH demonstrated interaction of Ser-70, Thr-18, and Pro-69 with C-H bonds; Gln-71, and Glu-113 with hydrogen bonds; while both Glu-114 and Glu-113 with salt-bridge connection. Permissible 1.0-1.5 Å range of RMSD fluctuation between 20 and 45 ns was obtained in simulation of IRS1 and IRS1-met complex confirmed that both complexes were stable during whole simulation process. RMSF result showed that except positions 57AA and 114AA, the binding of drug had no severe effects on the flexibility of the IRS1 and IRS1-met complex. The RoG value of compactness and rigidity showed little change in IRS1 protein. SASA value of IRS1 indicated non-significant fluctuation between IRS1 and drug MH means ligand (drug) and IRS1 receptor form stable structure. Hydrogen bond strength of IRS1 and IRS1-met was 81.2 and 76.4, respectively, which suggested stable interaction.
Collapse
Affiliation(s)
- Ritika Kumari Singh
- School of Biotechnology, Institute of Science, BHU, Varanasi, Uttar Pradesh 221005 India
| | | | - Arvind Kumar
- School of Biotechnology, Institute of Science, BHU, Varanasi, Uttar Pradesh 221005 India
| |
Collapse
|
|
7
|
Zhang N, Song GY, Yu QH, Fan XM, Zhang WS, Hu YJ, Chao TZ, Wu YY, Duan SY, Wang F, Du RP, Xu P. Evaluation of the lncRNA-miRNA-mRNA ceRNA network in lungs of miR-147 -/- mice. Front Pharmacol 2024; 15:1335374. [PMID: 38510653 PMCID: PMC10953689 DOI: 10.3389/fphar.2024.1335374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024] Open
Abstract
Background: Previous studies have documented important roles for microRNA-147 (miR-147) in inflammation, radiation-induced injury, cancer, and a range of other diseases. Murine lungs exhibit high levels of miRNA, mRNA, and lncRNA expression. However, very little research to date has focused on the lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks associated with miR-147, and the regulation of lncRNAs and miRNAs in this setting remains poorly understood. Methods: After establishing a miR-147-/- model mouse, samples of lung tissue were harvested for RNA-sequencing, and differentially expressed lncRNAs, miRNAs, and mRNAs were identified. The miRNA targets of these lncRNAs and the identified miRNAs were first overlapped to facilitate the prediction of target mRNAs, with analyses then examining the overlap between these targets and mRNAs that were differentially expressed. Then, these target mRNAs were subjected to pathway enrichment analyses. These results were ultimately used to establish a miR-147-related ceRNA network. Results: Relative to wild-type mice, the lungs of miR-147-/- mice exhibited 91, 43, and 71 significantly upregulated lncRNAs, miRNAs, and mRNAs, respectively, together with 114, 31, and 156 that were significantly downregulated. The lncRNA-miRNA-mRNA network established based on these results led to the identification of Kcnh6 as a differentially expressed hub gene candidate and enabled the identification of a range of regulatory relationships. KEGG pathway enrichment showed that the mRNA targets of differentially expressed lncRNAs and miRNAs in the mice were associated with tumor-related signaling, endometrial cancer, bladder cancer, and ErbB signaling. Conclusion: These results suggest that the identified ceRNA network in miR-147-/- mice shapes tumor-associated signaling activity, with miR-147 potentially regulating various lncRNAs and miRNAs through Kcnh6, ultimately influencing tumorigenesis. Future studies of the lncRNA, miRNA, and mRNA regulatory targets shown to be associated with miR-147 in the present study may ultimately lead to the identification of novel clinically relevant targets through which miR-147 shapes the pathogenesis of cancer and other diseases.
Collapse
Affiliation(s)
- Nan Zhang
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Gui-Yuan Song
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
| | - Qing-Hua Yu
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
- School of Public Health, Weifang Medical University, Weifang, Shandong, China
| | - Xin-Ming Fan
- Department of Radiotherapy, Zaozhuang Municipal Hospital, Zaozhuang, Shandong, China
| | - Wen-Shuo Zhang
- Department of Radiotherapy, Zaozhuang Municipal Hospital, Zaozhuang, Shandong, China
| | - Yong-Jian Hu
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, China
| | - Tian-Zhu Chao
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Yao-Yao Wu
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Shu-Yan Duan
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Fei Wang
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Rui-Peng Du
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Ping Xu
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| |
Collapse
|
|
8
|
Wu H, Li ZX, Fang K, Zhao ZY, Sun MC, Feng AQ, Leng ZY, Zhang ZH, Chu Y, Zhang L, Chen T, Xu MD. IGF-1-mediated FOXC1 overexpression induces stem-like properties through upregulating CBX7 and IGF-1R in esophageal squamous cell carcinoma. Cell Death Discov 2024; 10:102. [PMID: 38413558 PMCID: PMC10899262 DOI: 10.1038/s41420-024-01864-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 01/27/2024] [Accepted: 02/12/2024] [Indexed: 02/29/2024] Open
Abstract
Substantial evidence attests to the pivotal role of cancer stem cells (CSC) in both tumorigenesis and drug resistance. A member of the forkhead box (FOX) family, FOXC1, assumes significance in embryonic development and organogenesis. Furthermore, FOXC1 functions as an overexpressed transcription factor in various tumors, fostering proliferation, enhancing migratory capabilities, and promoting drug resistance, while maintaining stem-cell-like properties. Despite these implications, scant attention has been devoted to its role in esophageal squamous cell carcinoma. Our investigation revealed a pronounced upregulation of FOXC1 expression in ESCC, correlating with a poor prognosis. The downregulation of FOXC1 demonstrated inhibitory effects on ESCC tumorigenesis, proliferation, and tolerance to chemotherapeutic agents, concurrently reducing the levels of stemness-related markers CD133 and CD44. Further studies validated that FOXC1 induces ESCC stemness by transactivating CBX7 and IGF-1R. Additionally, IGF-1 activated the PI3K/AKT/NF-κB and MEK/ERK/NF-κB pathways through its binding to IGF-1R, thereby augmenting FOXC1 expression. Conversely, suppressing FOXC1 impeded ESCC stemness induced by IGF-1. The presence of a positive feedback loop, denoted by IGF-1-FOXC1-IGF-1R, suggests the potential of FOXC1 as a prognostic biomarker for ESCC. Taken together, targeting the IGF-1-FOXC1-IGF-1R axis emerges as a promising approach for anti-CSC therapy in ESCC.
Collapse
Affiliation(s)
- Hao Wu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Zhao-Xing Li
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Kang Fang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Zi-Ying Zhao
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Ming-Chuang Sun
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - An-Qi Feng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Zhu-Yun Leng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Ze-Hua Zhang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Yuan Chu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Li Zhang
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji 8 University, 200120, Shanghai, China
| | - Tao Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China.
| | - Mei-Dong Xu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China.
| |
Collapse
|
|
9
|
Nelson ZM, Leonard GD, Fehl C. Tools for investigating O-GlcNAc in signaling and other fundamental biological pathways. J Biol Chem 2024; 300:105615. [PMID: 38159850 PMCID: PMC10831167 DOI: 10.1016/j.jbc.2023.105615] [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: 06/09/2023] [Revised: 12/10/2023] [Accepted: 12/13/2023] [Indexed: 01/03/2024] Open
Abstract
Cells continuously fine-tune signaling pathway proteins to match nutrient and stress levels in their local environment by modifying intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc) sugars, an essential process for cell survival and growth. The small size of these monosaccharide modifications poses a challenge for functional determination, but the chemistry and biology communities have together created a collection of precision tools to study these dynamic sugars. This review presents the major themes by which O-GlcNAc influences signaling pathway proteins, including G-protein coupled receptors, growth factor signaling, mitogen-activated protein kinase (MAPK) pathways, lipid sensing, and cytokine signaling pathways. Along the way, we describe in detail key chemical biology tools that have been developed and applied to determine specific O-GlcNAc roles in these pathways. These tools include metabolic labeling, O-GlcNAc-enhancing RNA aptamers, fluorescent biosensors, proximity labeling tools, nanobody targeting tools, O-GlcNAc cycling inhibitors, light-activated systems, chemoenzymatic labeling, and nutrient reporter assays. An emergent feature of this signaling pathway meta-analysis is the intricate interplay between O-GlcNAc modifications across different signaling systems, underscoring the importance of O-GlcNAc in regulating cellular processes. We highlight the significance of O-GlcNAc in signaling and the role of chemical and biochemical tools in unraveling distinct glycobiological regulatory mechanisms. Collectively, our field has determined effective strategies to probe O-GlcNAc roles in biology. At the same time, this survey of what we do not yet know presents a clear roadmap for the field to use these powerful chemical tools to explore cross-pathway O-GlcNAc interactions in signaling and other major biological pathways.
Collapse
Affiliation(s)
- Zachary M Nelson
- Department of Chemistry, Wayne State University, Detroit, Michigan, USA
| | - Garry D Leonard
- Department of Chemistry, Wayne State University, Detroit, Michigan, USA
| | - Charlie Fehl
- Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
| |
Collapse
|
|
10
|
Martínez Báez A, Ayala G, Pedroza-Saavedra A, González-Sánchez HM, Chihu Amparan L. Phosphorylation Codes in IRS-1 and IRS-2 Are Associated with the Activation/Inhibition of Insulin Canonical Signaling Pathways. Curr Issues Mol Biol 2024; 46:634-649. [PMID: 38248343 PMCID: PMC10814773 DOI: 10.3390/cimb46010041] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/23/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
Insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) are signaling adaptor proteins that participate in canonical pathways, where insulin cascade activation occurs, as well as in non-canonical pathways, in which phosphorylation of substrates is carried out by a diverse array of receptors including integrins, cytokines, steroid hormones, and others. IRS proteins are subject to a spectrum of post-translational modifications essential for their activation, encompassing phosphorylation events in distinct tyrosine, serine, and threonine residues. Tyrosine residue phosphorylation is intricately linked to the activation of the insulin receptor cascade and its interaction with SH2 domains within a spectrum of proteins, including PI3K. Conversely, serine residue phosphorylation assumes a different function, serving to attenuate the effects of insulin. In this review, we have identified over 50 serine residues within IRS-1 that have been reported to undergo phosphorylation orchestrated by a spectrum of kinases, thereby engendering the activation or inhibition of different signaling pathways. Furthermore, we delineate the phosphorylation of over 10 distinct tyrosine residues at IRS-1 or IRS-2 in response to insulin, a process essential for signal transduction and the subsequent activation of PI3K.
Collapse
Affiliation(s)
- Anabel Martínez Báez
- Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico; (A.M.B.); (G.A.); (A.P.-S.)
| | - Guadalupe Ayala
- Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico; (A.M.B.); (G.A.); (A.P.-S.)
| | - Adolfo Pedroza-Saavedra
- Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico; (A.M.B.); (G.A.); (A.P.-S.)
| | - Hilda M. González-Sánchez
- CONAHCYT—Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico;
| | - Lilia Chihu Amparan
- Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico; (A.M.B.); (G.A.); (A.P.-S.)
| |
Collapse
|
|
11
|
Galal MA, Alouch SS, Alsultan BS, Dahman H, Alyabis NA, Alammar SA, Aljada A. Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance. Int J Mol Sci 2023; 24:15006. [PMID: 37834454 PMCID: PMC10573852 DOI: 10.3390/ijms241915006] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
This comprehensive review thoroughly explores the intricate involvement of insulin receptor (IR) isoforms and insulin-like growth factor receptors (IGFRs) in the context of the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway. This elaborate system encompasses ligands, receptors, and binding proteins, giving rise to a wide array of functions, including aspects such as carcinogenesis and chemoresistance. Detailed genetic analysis of IR and IGFR structures highlights their distinct isoforms, which arise from alternative splicing and exhibit diverse affinities for ligands. Notably, the overexpression of the IR-A isoform is linked to cancer stemness, tumor development, and resistance to targeted therapies. Similarly, elevated IGFR expression accelerates tumor progression and fosters chemoresistance. The review underscores the intricate interplay between IRs and IGFRs, contributing to resistance against anti-IGFR drugs. Consequently, the dual targeting of both receptors could present a more effective strategy for surmounting chemoresistance. To conclude, this review brings to light the pivotal roles played by IRs and IGFRs in cellular signaling, carcinogenesis, and therapy resistance. By precisely modulating these receptors and their complex signaling pathways, the potential emerges for developing enhanced anti-cancer interventions, ultimately leading to improved patient outcomes.
Collapse
Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Samhar Samer Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Buthainah Saad Alsultan
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Nouf Abdullah Alyabis
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Sarah Ammar Alammar
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| |
Collapse
|
|
12
|
Selven H, Busund LTR, Andersen S, Pedersen MI, Lombardi APG, Kilvaer TK. High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I-III Colon Cancer. Cancers (Basel) 2023; 15:cancers15051448. [PMID: 36900240 PMCID: PMC10000923 DOI: 10.3390/cancers15051448] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
Colon cancer is a common malignancy and a major contributor to human morbidity and mortality. In this study, we explore the expression and prognostic impact of IRS-1, IRS-2, RUNx3, and SMAD4 in colon cancer. Furthermore, we elucidate their correlations with miRs 126, 17-5p, and 20a-5p, which are identified as potential regulators of these proteins. Tumor tissue from 452 patients operated for stage I-III colon cancer was retrospectively collected and assembled into tissue microarrays. Biomarkers' expressions were examined by immunohistochemistry and analyzed using digital pathology. In univariate analyses, high expression levels of IRS1 in stromal cytoplasm, RUNX3 in tumor (nucleus and cytoplasm) and stroma (nucleus and cytoplasm), and SMAD4 in tumor (nucleus and cytoplasm) and stromal cytoplasm were related to increased disease-specific survival (DSS). In multivariate analyses, high expression of IRS1 in stromal cytoplasm, RUNX3 in tumor nucleus and stromal cytoplasm, and high expression of SMAD4 in tumor and stromal cytoplasm remained independent predictors of improved DSS. Surprisingly, with the exception of weak correlations (0.2 < r < 0.25) between miR-126 and SMAD4, the investigated markers were mostly uncorrelated with the miRs. However, weak to moderate/strong correlations (0.3 < r < 0.6) were observed between CD3 and CD8 positive lymphocyte density and stromal RUNX3 expression. High expression levels of IRS1, RUNX3, and SMAD4 are positive prognostic factors in stage I-III colon cancer. Furthermore, stromal expression of RUNX3 is associated with increased lymphocyte density, suggesting that RUNX3 is an important mediator during recruitment and activation of immune cells in colon cancer.
Collapse
Affiliation(s)
- Hallgeir Selven
- Department of Oncology, University Hospital of North Norway, 9038 Tromsø, Norway
- Department of Clinical Medicine, UiT The Arctic University of Norway, 9038 Tromsø, Norway
| | - Lill-Tove Rasmussen Busund
- Department of Pathology, University Hospital of North Norway, 9038 Tromsø, Norway
- Department of Medical Biology, UiT The Arctic University of Norway, 9038 Tromsø, Norway
| | - Sigve Andersen
- Department of Oncology, University Hospital of North Norway, 9038 Tromsø, Norway
- Department of Clinical Medicine, UiT The Arctic University of Norway, 9038 Tromsø, Norway
| | - Mona Irene Pedersen
- Department of Clinical Medicine, UiT The Arctic University of Norway, 9038 Tromsø, Norway
| | | | - Thomas Karsten Kilvaer
- Department of Oncology, University Hospital of North Norway, 9038 Tromsø, Norway
- Department of Clinical Medicine, UiT The Arctic University of Norway, 9038 Tromsø, Norway
- Correspondence: ; Tel.: +47-905-24-635
| |
Collapse
|
|
13
|
Clinton NA, Hameed SA, Agyei EK, Jacob JC, Oyebanji VO, Jabea CE. Crosstalk between the Intestinal Virome and Other Components of the Microbiota, and Its Effect on Intestinal Mucosal Response and Diseases. J Immunol Res 2022; 2022:7883945. [PMID: 36203793 PMCID: PMC9532165 DOI: 10.1155/2022/7883945] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
In recent years, there has been ample evidence illustrating the effect of microbiota on gut immunity, homeostasis, and disease. Most of these studies have engaged more efforts in understanding the role of the bacteriome in gut mucosal immunity and disease. However, studies on the virome and its influence on gut mucosal immunity and pathology are still at infancy owing to limited metagenomic tools. Nonetheless, the existing studies on the virome have largely been focused on the bacteriophages as these represent the main component of the virome with little information on endogenous retroviruses (ERVs) and eukaryotic viruses. In this review, we describe the gut virome, and its role in gut mucosal response and disease progression. We also explore the crosstalk between the virome and other microorganisms in the gut mucosa and elaborate on how these interactions shape the gut mucosal immunity going from bacteriophages through ERVs to eukaryotic viruses. Finally, we elucidate the potential contribution of this crosstalk in the pathogenesis of inflammatory bowel diseases and colon cancer.
Collapse
Affiliation(s)
- Njinju Asaba Clinton
- Health and Empowerment Foundation, Cameroon
- Mbonge District Hospital, Cameroon
- University of Buea, Cameroon
| | | | - Eugene Kusi Agyei
- Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Ghana
| | | | | | - Cyril Ekabe Jabea
- Health and Empowerment Foundation, Cameroon
- Mbonge District Hospital, Cameroon
- University of Buea, Cameroon
| |
Collapse
|
|
14
|
Liu R, Bai L, Liu M, Wang R, Wu Y, Li Q, Ba Y, Zhang H, Zhou G, Yu F, Huang H. Combined exposure of lead and high-fat diet enhanced cognitive decline via interacting with CREB-BDNF signaling in male rats. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 304:119200. [PMID: 35364187 DOI: 10.1016/j.envpol.2022.119200] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/03/2022] [Accepted: 03/21/2022] [Indexed: 06/14/2023]
Abstract
The health risks to populations induced by lead (Pb) and high-fat diets (HFD) have become a global public health problem. Pb and HFD often co-exist and are co-occurring risk factors for cognitive impairment. This study investigates effect of combined Pb and HFD on cognitive function, and explores the underlying mechanisms in terms of regulatory components of synaptic plasticity and insulin signaling pathway. We showed that the co-exposure of Pb and HFD further increased blood Pb levels, caused body weight loss and dyslipidemia. The results from Morris water maze (MWM) test and Nissl staining disclosed that Pb and HFD each contributed to cognitive deficits and neuronal damage and combined exposure enhanced this toxic injury. Pb and HFD decreased the levels of synapsin-1, GAP-43 and PSD-95 protein related to synaptic properties and SIRT1, NMDARs, phosphorylated CREB and BDNF related to synaptic plasticity regulatory, and these decreases was greater when combined exposure. Additionally, we revealed that Pb and HFD promoted IRS-1 phosphorylation and subsequently reduced downstream PI3K-Akt kinases phosphorylation in hippocampus and cortex of rats, and this process was aggravated when co-exposure. Collectively, our data suggested that combined exposure of Pb and HFD enhanced cognitive deficits, pointing to additive effects in rats than the individual stress effects related to multiple signaling pathways with CREB-BDNF signaling as the hub. This study emphasizes the need to evaluate the effects of mixed exposures on brain function in realistic environment and to better inform prevention of neurological disorders via modulating central pathway, such as CREB/BDNF signaling.
Collapse
Affiliation(s)
- Rundong Liu
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Lin Bai
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Mengchen Liu
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Ruike Wang
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Yingying Wu
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Qiong Li
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Yue Ba
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Huizhen Zhang
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Guoyu Zhou
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Fangfang Yu
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Hui Huang
- Department of Environmental Health &Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.
| |
Collapse
|
|
15
|
Shrestha Bhattarai T, Shamu T, Gorelick AN, Chang MT, Chakravarty D, Gavrila EI, Donoghue MTA, Gao J, Patel S, Gao SP, Reynolds MH, Phillips SM, Soumerai T, Abida W, Hyman DM, Schram AM, Solit DB, Smyth LM, Taylor BS. AKT mutant allele-specific activation dictates pharmacologic sensitivities. Nat Commun 2022; 13:2111. [PMID: 35440569 PMCID: PMC9018718 DOI: 10.1038/s41467-022-29638-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 03/25/2022] [Indexed: 12/13/2022] Open
Abstract
AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.
Collapse
Affiliation(s)
- Tripti Shrestha Bhattarai
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tambudzai Shamu
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexander N Gorelick
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Matthew T Chang
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Loxo Oncology at Lilly, Stamford, CT, USA
| | - Debyani Chakravarty
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elena I Gavrila
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mark T A Donoghue
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - JianJong Gao
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Swati Patel
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sizhi Paul Gao
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Margaret H Reynolds
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sarah M Phillips
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tara Soumerai
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Massachusetts General Hospital, Boston, MA, USA
| | - Wassim Abida
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David M Hyman
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
- Loxo Oncology at Lilly, Stamford, CT, USA
| | - Alison M Schram
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David B Solit
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Lillian M Smyth
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Loxo Oncology at Lilly, Stamford, CT, USA
| | - Barry S Taylor
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, USA.
- Loxo Oncology at Lilly, Stamford, CT, USA.
| |
Collapse
|
|
16
|
Wang Y, Ai D, Li S. CirRNA circFAM126A Exerts Oncogenic Functions in NSCLC to Upregulate IRS2. Biochem Genet 2022; 60:2364-2382. [PMID: 35397054 DOI: 10.1007/s10528-022-10212-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/24/2022] [Indexed: 12/24/2022]
Abstract
Non-small cell lung cancer (NSCLC) is a common histological subtype of lung cancer, which occupies 80-85% of the proportion in all lung cancer cases. Therefore, this study was designed to clarify the role and underlying molecular mechanisms of circFAM126A in NSCLC. The real-time quantitative polymerase chain reaction (RT-qPCR) assay was conducted to assess circFAM126A, FAM126A, miR-613, and IRS2 expression in NSCLC tissues and cells. The proliferation ability of cells was measured by MTT, EdU, and colony-forming assays. The flow cytometry assay was performed to evaluate cell cycle distribution and apoptosis of NSCLC cells. The migration and invasion were determined by wound healing and transwell matrigel assays, respectively. The interaction relationship between miR-613 and circFAM126A or IRS2 was analyzed by dual-luciferase reporter and RNA pull-down assays. Tumorigenesis in nude mice was conducted to clarify the functional roles of circFAM126A inhibition in vivo. CircFAM126A was obviously overexpressed in NSCLC tissues and cells when compared with controls. The loss-of-functional experiments suggested that knockdown of circFAM126A suppressed proliferation, migration and invasion, as well as caused apoptosis and cell cycle arrest in NSCLC cells, which was abolished by silencing of miR-613. In addition, IRS2 was a target gene of miR-613. Overexpression of miR-613 exerted carcinoma inhibitor role in NSCLC by inhibition of IRS2 expression. Consistently, the silencing of circFAM126A also functioned anti-tumorigenic roles in nude mice in vivo. Mechanistically, circFAM126A could function as a miRNA sponge for miR-613 to regulate the expression of IRS2, thereby regulating proliferation, migration, invasion, apoptosis, and cell cycle arrest in NSCLC cells.
Collapse
Affiliation(s)
- Yujing Wang
- Department of Pediatrics, The First People's Hospital of Chong Qing Liang Jiang New Area, No. 199, Renxing Road, Renhe Street, Liangjiang New District, Chongqing, 401121, China
| | - Dehui Ai
- Department of Respiration and Oncology, Chongqing DongNan Hospital, Chongqing, 401336, China
| | - Shaoxiong Li
- Department of Respiratory Medicine, Chongqing Qijiang District People's Hospital, No.54, Tuwan Branch Road, Gushan Street, Qijiang District, Chongqing, 401420, China.
| |
Collapse
|
|
17
|
Dao T, Mun SS, Molvi Z, Korontsvit T, Klatt MG, Khan AG, Nyakatura EK, Pohl MA, White TE, Balderes PJ, Lorenz IC, O'Reilly RJ, Scheinberg DA. A TCR mimic monoclonal antibody reactive with the "public" phospho-neoantigen pIRS2/HLA-A*02:01 complex. JCI Insight 2022; 7:151624. [PMID: 35260532 PMCID: PMC8983142 DOI: 10.1172/jci.insight.151624] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
Phosphopeptides derived from dysregulated protein phosphorylation in cancer cells can be processed and presented by MHC class I and class II molecules and, therefore, represent an untapped class of tumor-specific antigens that could be used as widely expressed “public” cancer neoantigens (NeoAgs). We generated a TCR mimic (TCRm) mAb, 6B1, specific for a phosphopeptide derived from insulin receptor substrate 2 (pIRS2) presented by HLA-A*02:01. The pIRS2 epitope’s presentation by HLA-A*02:01 was confirmed by mass spectrometry. The TCRm 6B1 specifically bound to pIRS2/HLA-A2 complex on tumor cell lines that expressed pIRS2 in the context of HLA-A*02:01. Bispecific mAbs engaging CD3 of T cells were able to kill tumor cell lines in a pIRS2- and HLA-A*02:01–restricted manner. Structure modeling shows a prerequisite for an arginine or lysine at the first position to bind mAb. Therefore, 6B1 could recognize phosphopeptides derived from various phosphorylated proteins with similar amino acid compositions. This raised the possibility that a TCRm specific for the pIRS2/HLA-A2 complex could target a range of phosphopeptides presented by HLA-A*02:01 in various tumor cells. This is the first TCRm mAb to our knowledge targeting a phosphopeptide/MHC class I complex; the potential of this class of agents for clinical applications warrants further investigation.
Collapse
Affiliation(s)
- Tao Dao
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
| | - Sung Soo Mun
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
| | - Zaki Molvi
- Immunology Program, Weill Cornell Medicine, New York, New York, USA
| | - Tatyana Korontsvit
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
| | - Martin G Klatt
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
| | - Abdul G Khan
- Tri-Institutional Therapeutics Discovery Institute, New York, New York, USA
| | | | - Mary Ann Pohl
- Tri-Institutional Therapeutics Discovery Institute, New York, New York, USA
| | - Thomas E White
- Tri-Institutional Therapeutics Discovery Institute, New York, New York, USA
| | - Paul J Balderes
- Tri-Institutional Therapeutics Discovery Institute, New York, New York, USA
| | - Ivo C Lorenz
- Tri-Institutional Therapeutics Discovery Institute, New York, New York, USA
| | - Richard J O'Reilly
- Immunology Program, Weill Cornell Medicine, New York, New York, USA.,Weill Cornell Medicine, New York, New York, USA
| | - David A Scheinberg
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.,Weill Cornell Medicine, New York, New York, USA
| |
Collapse
|
|
18
|
Dolatabadi S, Jonasson E, Andersson L, Luna Santamaría M, Lindén M, Österlund T, Åman P, Ståhlberg A. FUS-DDIT3 Fusion Oncoprotein Expression Affects JAK-STAT Signaling in Myxoid Liposarcoma. Front Oncol 2022; 12:816894. [PMID: 35186752 PMCID: PMC8851354 DOI: 10.3389/fonc.2022.816894] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/06/2022] [Indexed: 11/25/2022] Open
Abstract
Myxoid liposarcoma is one of the most common sarcoma entities characterized by FET fusion oncogenes. Despite a generally favorable prognosis of myxoid liposarcoma, chemotherapy resistance remains a clinical problem. This cancer stem cell property is associated with JAK-STAT signaling, but the link to the myxoid-liposarcoma-specific FET fusion oncogene FUS-DDIT3 is not known. Here, we show that ectopic expression of FUS-DDIT3 resulted in elevated levels of STAT3 and phosphorylated STAT3. RNA sequencing identified 126 genes that were regulated by both FUS-DDIT3 expression and JAK1/2 inhibition using ruxolitinib. Sixty-six of these genes were connected in a protein interaction network. Fifty-three and 29 of these genes were confirmed as FUS-DDIT3 and STAT3 targets, respectively, using public chromatin immunoprecipitation sequencing data sets. Enriched gene sets among the 126 regulated genes included processes related to cytokine signaling, adipocytokine signaling, and chromatin remodeling. We validated CD44 as a target gene of JAK1/2 inhibition and as a potential cancer stem cell marker in myxoid liposarcoma. Finally, we showed that FUS-DDIT3 interacted with phosphorylated STAT3 in association with subunits of the SWI/SNF chromatin remodeling complex and PRC2 repressive complex. Our data show that the function of FUS-DDIT3 is closely connected to JAK-STAT signaling. Detailed deciphering of molecular mechanisms behind tumor progression opens up new avenues for targeted therapies in sarcomas and leukemia characterized by FET fusion oncogenes.
Collapse
Affiliation(s)
- Soheila Dolatabadi
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Emma Jonasson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Lisa Andersson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Manuel Luna Santamaría
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Malin Lindén
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Tobias Österlund
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Pierre Åman
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Anders Ståhlberg
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| |
Collapse
|
|
19
|
Lessi F, Aretini P, Rizzo M, Morelli M, Menicagli M, Franceschi S, Mazzanti CM. Analysis of exosome-derived microRNAs reveals insights of intercellular communication during invasion of breast, prostate and glioblastoma cancer cells. Cell Adh Migr 2021; 15:180-201. [PMID: 34157951 PMCID: PMC8224203 DOI: 10.1080/19336918.2021.1935407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 04/08/2021] [Accepted: 05/20/2021] [Indexed: 12/28/2022] Open
Abstract
MiRNAs represent a mechanism that regulates gene expression in many pathological conditions. Exosomes are known to be secreted from all types of cells, and the exosomes-released molecules are crucial messengers that can regulate cellular processes. We investigated the miRNAs content of exosomes released by cancer cells during the invasion . An invasion stimulus has been generated through scratches created on the confluent cells of cancer cell lines: glioblastoma, breast and prostate cancers.Several miRNAs were found to be significantly differentially abundant during the cell invasion , both in common among different cell lines and exclusive. Understanding the language codes among cells involved in invasion can lead to the development of therapies that can inhibit cellular communication, slowing or eventually stopping their activity.
Collapse
Affiliation(s)
| | | | - Milena Rizzo
- Institute of Clinical Physiology (IFC), CNR, Pisa, Italy
| | | | | | | | | |
Collapse
|
|
20
|
Liu Y, Mu S, Chen W, Liu S, Cong Y, Liu J, Jia N. Saponins of Momordica charantia increase insulin secretion in INS-1 pancreatic β-cells via the PI3K/Akt/FoxO1 signaling pathway. ENDOCRINOL DIAB NUTR 2021; 68:329-337. [PMID: 34556263 DOI: 10.1016/j.endien.2021.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 05/06/2020] [Indexed: 11/16/2022]
Abstract
Saponins are the main bioactive substances with anti-hyperglycemic activities of Momordica charantia. This study aimed to verify the effects of M. charantia saponins on insulin secretion and explore the potential underlying mechanisms in INS-1 pancreatic β-cells. We injured INS-1 cells with 33.3mM glucose and then treated them with saponins. Saponins improved cell morphology and viability as demonstrated by inverted microscopy and CCK8 detection and significantly increased insulin secretion in a concentration-dependent manner as shown by ELISA. Thus, we obtained the optimal concentration for the subsequent experiments. Potential mechanisms were explored by immunofluorescence, western blotting, and RT-qPCR techniques. First, saponins increased the mRNA and protein levels of IRS-2 but decreased the serine 731 phosphorylation level of IRS-2. Moreover, saponins increased the phosphorylation of Akt protein and decreased the protein level of FoxO1, which were both reversed by the PI3K inhibitor ly294002. Furthermore, saponins increased the protein level of the downstream molecule and insulin initiating factor PDX-1, which was also reversed by ly294002. Saponins also increased Akt and PDX-1 mRNA and decreased FoxO1 mRNA, which were both reversed by ly294002. Saponins increased glucose-stimulated insulin secretion (GSIS) and intracellular insulin content, which were reversed by ly294002, as determined by ELISA. The immunofluorescence results also confirmed this tendency. In conclusion, our findings improve our understanding of the function of saponins in INS-1 pancreatic β-cells and suggest that saponins may increase insulin secretion via the PI3K/Akt/FoxO1 signaling pathway.
Collapse
Affiliation(s)
- Yufan Liu
- Traditional Chinese Medicine College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shumin Mu
- Department of Endocrinology, Hospital Affiliated to Shandong Traditional Chinese Medicine University, Jinan, China.
| | - Wenbin Chen
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Shiyin Liu
- First Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuxuan Cong
- Department of Endocrinology, Weihai Hospital of Traditional Chinese Medicine, Weihai, China
| | - Jiajia Liu
- Department of Endocrinology, People's Hospital of Gaotang County, Liaocheng, China
| | - Ning Jia
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| |
Collapse
|
|
21
|
Gen Y, Muramatsu T, Inoue J, Inazawa J. miR-766-5p targets super-enhancers by downregulating CBP and BRD4. Cancer Res 2021; 81:5190-5201. [PMID: 34353856 DOI: 10.1158/0008-5472.can-21-0649] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/29/2021] [Accepted: 07/28/2021] [Indexed: 11/16/2022]
Abstract
Super-enhancers (SE) are clusters of transcription enhancers that drive gene expression. SEs are typically characterized by high levels of acetylation of histone H3 lysine 27 (H3K27ac), which is catalyzed by the histone lysine acetyltransferase CREB binding protein (CBP). Cancer cells frequently acquire tumor-specific SEs at key oncogenes, such as MYC, which induce several hallmarks of cancer. BRD4 is recruited to SEs and consequently functions as an epigenetic reader to promote transcription of SE-marked genes in cancer cells. miRNAs can be potent candidates for nucleic acid therapeutics for cancer. We previously identified miR-766-5p as a miRNA that downregulated MYC expression and inhibited cancer cell growth in vitro. In this study, we show that miR-766-5p directly targets CBP and BRD4. Concurrent suppression of CBP and BRD4 cooperatively downregulated MYC expression in cancer cells but not in normal cells. Chromatin immunoprecipitation analysis revealed that miR-766-5p reduced levels of H3K27ac at MYC SEs via CBP suppression. Moreover, miR-766-5p suppressed expression of a BRD4-NUT fusion protein that drives NUT midline carcinoma (NMC). In vivo administration of miR-766-5p suppressed tumor growth in two xenograft models. Collectively, these data suggest that targeting SEs using miR-766-5p-based therapeutics may serve as an effective strategy for the treatment of MYC-driven cancers.
Collapse
Affiliation(s)
- Yasuyuki Gen
- Department of Molecular Cytogenetics, Tokyo Medical and Dental University
| | - Tomoki Muramatsu
- Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University
| | - Jun Inoue
- Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University
| | - Johji Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU)
| |
Collapse
|
|
22
|
Li L, Sun Y, Zhang Y, Wang W, Ye C. Mutant Huntingtin Impairs Pancreatic β-cells by Recruiting IRS-2 and Disturbing the PI3K/AKT/FoxO1 Signaling Pathway in Huntington's Disease. J Mol Neurosci 2021; 71:2646-2658. [PMID: 34331233 DOI: 10.1007/s12031-021-01869-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/09/2021] [Indexed: 10/20/2022]
Abstract
Patients with Huntington's disease (HD) have an increased incidence of diabetes. However, the molecular mechanisms of pancreatic β-cell dysfunction have not been entirely clarified. Revealing the pathogenesis of diabetes can provide a novel understanding of the onset and progression of HD, as well as potential clues for the development of new therapeutics. Here, we demonstrated that the mouse pancreatic insulinoma cell line NIT-1 expressing N-terminal mutant huntingtin (mHTT) containing 160 polyglutamine (160Q cells) displayed lower cell proliferative ability than the cells expressing N-terminal wild-type HTT containing 20 polyglutamine (20Q cells). In addition, 160Q cells were more prone to apoptosis and exhibited deficient glucose-stimulated insulin expression and secretion. Furthermore, insulin signaling molecule insulin receptor substrate 2 (IRS-2) expression decreased and was recruited into mHTT aggregates. Consequently, glucose stimulation failed to activate the downstream molecule phosphatidylinositol-3 kinase (PI3K) in 160Q cells, leading to reduced phosphorylation levels of serine-threonine protein kinase AKT and forkhead box protein O1 (FoxO1). These data indicate that activation of the glucose-stimulated PI3K/AKT/FoxO1 signaling pathway is significantly blocked in pancreatic β-cells in HD. Importantly, insulin treatment inhibited the aggregation of mHTT and significantly improved the activation of PI3K/AKT/FoxO1 signaling in 160Q cells. These results suggest that the inhibition of the PI3K/AKT/FoxO1 pathway might be due to the recruitment of IRS-2 into mHTT aggregates in HD β-cells, ultimately contributing to the impairment of pancreatic β-cells. In conclusion, our work provides new insight into the underlying mechanisms of the high incidence of diabetes and abnormal glucose homeostasis in HD.
Collapse
Affiliation(s)
- Li Li
- School of Biomedical Sciences, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong S.A.R., P.R. of China
| | - Yun Sun
- Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. of China
| | - Yinong Zhang
- Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. of China
| | - Weixi Wang
- Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. of China
| | - Cuifang Ye
- Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. of China.
| |
Collapse
|
|
23
|
Engelhard VH, Obeng RC, Cummings KL, Petroni GR, Ambakhutwala AL, Chianese-Bullock KA, Smith KT, Lulu A, Varhegyi N, Smolkin ME, Myers P, Mahoney KE, Shabanowitz J, Buettner N, Hall EH, Haden K, Cobbold M, Hunt DF, Weiss G, Gaughan E, Slingluff CL. MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma. J Immunother Cancer 2021; 8:jitc-2019-000262. [PMID: 32385144 PMCID: PMC7228659 DOI: 10.1136/jitc-2019-000262] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides. METHODS Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3126-134) was determined by 51Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA-IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund's adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay. RESULTS pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3126-134 controlled outgrowth of a tumor xenograft. The pIRS21097-1105 peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3-4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS21097-1105 peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3126-134 peptide in 2/12 patients (17%, 90% CI 3% to 44%). CONCLUSION This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3126-134 and pIRS21097-1105, and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses. TRIAL REGISTRATION NUMBER NCT01846143.
Collapse
Affiliation(s)
- Victor H Engelhard
- Beirne Carter Center for Immunology Research and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Rebecca C Obeng
- Beirne Carter Center for Immunology Research and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Kara L Cummings
- Beirne Carter Center for Immunology Research and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Gina R Petroni
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Angela L Ambakhutwala
- Beirne Carter Center for Immunology Research and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Kimberly A Chianese-Bullock
- Department of Surgery/Division of Surgical Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Kelly T Smith
- Department of Surgery/Division of Surgical Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Amanda Lulu
- Beirne Carter Center for Immunology Research and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Nikole Varhegyi
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Mark E Smolkin
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Paisley Myers
- Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA
| | - Keira E Mahoney
- Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA
| | - Jeffrey Shabanowitz
- Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA
| | - Nico Buettner
- 7Medical Research Council Centre for Immune Regulation and Clinical Immunology Service, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Emily H Hall
- Office of Clinical Research, University Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Kathleen Haden
- Department of Surgery/Division of Surgical Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Mark Cobbold
- 7Medical Research Council Centre for Immune Regulation and Clinical Immunology Service, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Donald F Hunt
- Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA
| | - Geoffrey Weiss
- Medicine/Division of Hematology-Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Elizabeth Gaughan
- Medicine/Division of Hematology-Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Craig L Slingluff
- Department of Surgery/Division of Surgical Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| |
Collapse
|
|
24
|
Paston SJ, Brentville VA, Symonds P, Durrant LG. Cancer Vaccines, Adjuvants, and Delivery Systems. Front Immunol 2021; 12:627932. [PMID: 33859638 PMCID: PMC8042385 DOI: 10.3389/fimmu.2021.627932] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/12/2021] [Indexed: 12/11/2022] Open
Abstract
Vaccination was first pioneered in the 18th century by Edward Jenner and eventually led to the development of the smallpox vaccine and subsequently the eradication of smallpox. The impact of vaccination to prevent infectious diseases has been outstanding with many infections being prevented and a significant decrease in mortality worldwide. Cancer vaccines aim to clear active disease instead of aiming to prevent disease, the only exception being the recently approved vaccine that prevents cancers caused by the Human Papillomavirus. The development of therapeutic cancer vaccines has been disappointing with many early cancer vaccines that showed promise in preclinical models often failing to translate into efficacy in the clinic. In this review we provide an overview of the current vaccine platforms, adjuvants and delivery systems that are currently being investigated or have been approved. With the advent of immune checkpoint inhibitors, we also review the potential of these to be used with cancer vaccines to improve efficacy and help to overcome the immune suppressive tumor microenvironment.
Collapse
Affiliation(s)
| | | | - Peter Symonds
- Biodiscovery Institute, Scancell Limited, Nottingham, United Kingdom
| | - Lindy G. Durrant
- Biodiscovery Institute, University of Nottingham, Faculty of Medicine and Health Sciences, Nottingham, United Kingdom
| |
Collapse
|
|
25
|
Li J, Yang Y, Xu D, Cao L. hsa_circ_0023409 Accelerates Gastric Cancer Cell Growth and Metastasis Through Regulating the IRS4/PI3K/AKT Pathway. Cell Transplant 2021; 30:963689720975390. [PMID: 33439739 PMCID: PMC7809302 DOI: 10.1177/0963689720975390] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/08/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is a big threat to human life and health. Circular RNAs (circRNAs), a subclass of noncoding RNAs, were reported to play a critical role in GC progression. Here, we investigated the role of a novel circRNA named hsa_circ_0023409 in GC and its mechanism. Hsa_circ_0023409 expression in GC and adjacent tissues was examined by quantitative real-time polymerase chain reaction and in situ hybridization. The functions of hsa_circ_0023409 in GC cells were assessed both in vitro and in vivo. Immunofluorescence staining was performed for the localization of hsa_circ_0023409 and miR-542-3p in cells. The interaction between hsa_circ_0023409 and miR-542-3p, and miR-542-3p and insulin receptor substrate 4 (IRS4) was detected by dual-luciferase reporter assay. The effect of hsa_circ_0023409, miR-542-3p, and IRS4 on IRS4/phosphatidylinositol 3-kinase (PI3K)/AKT pathway was detected by western blot. The results showed that hsa_circ_0023409 was mainly located in cytoplasm and highly expressed in GC tissues and cells. Moreover, hsa_circ_0023409 showed positive correlation with tumor size, histological grade, and tumor-node-metastasis staging of GC patients. Functional studies showed that hsa_circ_0023409 promoted cell viability, proliferation, migration, and invasion and suppressed apoptosis in GC. Mechanism studies demonstrated that hsa_circ_0023409 upregulated IRS4 via sponging miR-542-3p in GC cells. Furthermore, IRS4 overexpression activated the PI3K/AKT pathway and reversed the inhibitory effect of hsa_circ_0023409 knockdown on the PI3K/AKT pathway. Taken together, we prove that hsa_circ_0023409 activates IRS4/PI3K/AKT pathway by acting as a sponge for miR-542-3p, thus promoting GC progression, indicating that hsa_circ_0023409 may serve as a potential target for treatment of GC and prognosis of GC patients.
Collapse
Affiliation(s)
- Jian Li
- Department of Gastrointestinal Surgery, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang city, Jiangxi Province, China
| | - Yongjing Yang
- Department of Radiation Oncology, Jilin Provincial Cancer Hospital, Changchun City, Jilin Province, China
| | - Dequan Xu
- Department of Radiation Oncology, Jilin Provincial Cancer Hospital, Changchun City, Jilin Province, China
| | - Ling Cao
- Department of Radiation Oncology, Jilin Provincial Cancer Hospital, Changchun City, Jilin Province, China
| |
Collapse
|
|
26
|
Meng Y, Hu X, Li S, Zeng X, Qiu L, Wei M, Wang Z, Han J. miR-203 inhibits cell proliferation and ERK pathway in prostate cancer by targeting IRS-1. BMC Cancer 2020; 20:1028. [PMID: 33109107 PMCID: PMC7590475 DOI: 10.1186/s12885-020-07472-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 09/29/2020] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Prostate cancer (PCa) is one of the most common types of cancer in men. In the course of the development and progression of this disease, abnormal expression of miR-203 is usually accompanied. However, its role in prostate tumorigenesis and the underlying mechanism are poorly understood. METHODS Dual luciferase reporter gene analysis was used to detect miR-203 binding site in insulin receptor substrates 1 (IRS-1). Cell proliferation was assessed by MTT assay in PCa cells with either IRS-1 knockdown or miR-203 overexpression. IRS-1 and other proteins expression in PCa cells was assessed by Western Blot. RESULTS we found that the insulin receptor substrates 1 (IRS-1) is a novel target of miR-203 in PCa and miR-203 can specifically bind to the 3'UTR region of the IRS-1 thus suppresses its expression. Moreover, we demonstrate that miR-203 functions as a tumor suppressor by directly targeting IRS-1 to inhibit cell proliferation and migration which results in PCa cell cycle arrest. Importantly, miR-203 overexpression blocks ERK signalling pathway by down-regulating IRS-1 expression. CONCLUSIONS Our results show a novel link between miR-203 and IRS-1, and reveal the importance of strict control of IRS - 1 by miR-203 in the progression of PCa, suggesting miR-203 may act as a promising target for the diagnosis and treatment of advanced PCa.
Collapse
Affiliation(s)
- Yang Meng
- Department of Abdominal Oncology and Laboratory of Epigenetics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Xiaoyan Hu
- Department of Abdominal Oncology and Laboratory of Epigenetics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Shasha Li
- Department of Abdominal Oncology and Laboratory of Epigenetics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Xinyi Zeng
- Department of Abdominal Oncology and Laboratory of Epigenetics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Lei Qiu
- Department of Abdominal Oncology and Laboratory of Epigenetics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Mingtian Wei
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Ziqing Wang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Junhong Han
- Department of Abdominal Oncology and Laboratory of Epigenetics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
| |
Collapse
|
|
27
|
Saponins of Momordica charantia increase insulin secretion in INS-1 pancreatic β-cells via the PI3K/Akt/FoxO1 signaling pathway. ACTA ACUST UNITED AC 2020; 68:329-337. [PMID: 33069631 DOI: 10.1016/j.endinu.2020.05.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 05/06/2020] [Accepted: 05/06/2020] [Indexed: 12/20/2022]
Abstract
Saponins are the main bioactive substances with anti-hyperglycemic activities of Momordica charantia. This study aimed to verify the effects of M. charantia saponins on insulin secretion and explore the potential underlying mechanisms in INS-1 pancreatic β-cells. We injured INS-1 cells with 33.3mM glucose and then treated them with saponins. Saponins improved cell morphology and viability as demonstrated by inverted microscopy and CCK8 detection and significantly increased insulin secretion in a concentration-dependent manner as shown by ELISA. Thus, we obtained the optimal concentration for the subsequent experiments. Potential mechanisms were explored by immunofluorescence, western blotting, and RT-qPCR techniques. First, saponins increased the mRNA and protein levels of IRS-2 but decreased the serine 731 phosphorylation level of IRS-2. Moreover, saponins increased the phosphorylation of Akt protein and decreased the protein level of FoxO1, which were both reversed by the PI3K inhibitor ly294002. Furthermore, saponins increased the protein level of the downstream molecule and insulin initiating factor PDX-1, which was also reversed by ly294002. Saponins also increased Akt and PDX-1 mRNA and decreased FoxO1 mRNA, which were both reversed by ly294002. Saponins increased glucose-stimulated insulin secretion (GSIS) and intracellular insulin content, which were reversed by ly294002, as determined by ELISA. The immunofluorescence results also confirmed this tendency. In conclusion, our findings improve our understanding of the function of saponins in INS-1 pancreatic β-cells and suggest that saponins may increase insulin secretion via the PI3K/Akt/FoxO1 signaling pathway.
Collapse
|
|
28
|
Eyler CE, Matsunaga H, Hovestadt V, Vantine SJ, van Galen P, Bernstein BE. Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance. Genome Biol 2020; 21:174. [PMID: 32669109 PMCID: PMC7364565 DOI: 10.1186/s13059-020-02085-1] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 06/25/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Tumors can evolve and adapt to therapeutic pressure by acquiring genetic and epigenetic alterations that may be transient or stable. A precise understanding of how such events contribute to intratumoral heterogeneity, dynamic subpopulations, and overall tumor fitness will require experimental approaches to prospectively label, track, and characterize resistant or otherwise adaptive populations at the single-cell level. In glioblastoma, poor efficacy of receptor tyrosine kinase (RTK) therapies has been alternatively ascribed to genetic heterogeneity or to epigenetic transitions that circumvent signaling blockade. RESULTS We combine cell lineage barcoding and single-cell transcriptomics to trace the emergence of drug resistance in stem-like glioblastoma cells treated with RTK inhibitors. Whereas a broad variety of barcoded lineages adopt a Notch-dependent persister phenotype that sustains them through early drug exposure, rare subclones acquire genetic changes that enable their rapid outgrowth over time. Single-cell analyses reveal that these genetic subclones gain copy number amplifications of the insulin receptor substrate-1 and substrate-2 (IRS1 or IRS2) loci, which activate insulin and AKT signaling programs. Persister-like cells and genomic amplifications of IRS2 and other loci are evident in primary glioblastomas and may underlie the inefficacy of targeted therapies in this disease. CONCLUSIONS A method for combined lineage tracing and scRNA-seq reveals the interplay between complementary genetic and epigenetic mechanisms of resistance in a heterogeneous glioblastoma tumor model.
Collapse
Affiliation(s)
- Christine E. Eyler
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
- Broad Institute of Harvard and MIT, Cambridge, MA USA
| | - Hironori Matsunaga
- Broad Institute of Harvard and MIT, Cambridge, MA USA
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Volker Hovestadt
- Broad Institute of Harvard and MIT, Cambridge, MA USA
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Samantha J. Vantine
- Broad Institute of Harvard and MIT, Cambridge, MA USA
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Peter van Galen
- Broad Institute of Harvard and MIT, Cambridge, MA USA
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Bradley E. Bernstein
- Broad Institute of Harvard and MIT, Cambridge, MA USA
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| |
Collapse
|
|
29
|
Barker RM, Holly JMP, Biernacka KM, Allen-Birt SJ, Perks CM. Mini Review: Opposing Pathologies in Cancer and Alzheimer's Disease: Does the PI3K/Akt Pathway Provide Clues? Front Endocrinol (Lausanne) 2020; 11:403. [PMID: 32655497 PMCID: PMC7324530 DOI: 10.3389/fendo.2020.00403] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 05/20/2020] [Indexed: 12/30/2022] Open
Abstract
This minireview is a brief overview examining the roles of insulin-like growth factors (IGFs) and the PI3K/Akt pathway in two apparently unconnected diseases: Alzheimer's dementia and cancer. For both, increased age is a major risk factor, and, in accord with the global rise in average life expectancy, their prevalence is also increasing. Cancer, however, involves excessive cell proliferation and metastasis, whereas Alzheimer's disease (AD) involves cell death and tissue destruction. The apparent "inverse" nature of these disease states is examined here, but also some important commonalities in terms of the PI3K/Akt pathway, glucose utilization and cell deregulation/death. The focus here is on four key molecules associated with this pathway; notably, the insulin receptor substrate 1 (IRS-1), cellular tumor antigen p53 (p53), peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) and low-density lipoprotein receptor-related protein-1 (LRP1), all previously identified as potential therapeutic targets for both diseases. The insulin-resistant state, commonly reported in AD brain, results in neuronal glucose deprivation, due to a dampening down of the PI3K/Akt pathway, including overactivity of the mammalian target of rapamycin 1 (mTORC1) complex, hyperphosphorylation of p53 and neuronal death. This contrasts with cancer, where there is overstimulation of the PI3K/Akt pathway and the suppression of mTORC1 and p53, enabling abundant energy and unrestrained cell proliferation. Although these disease states appear to be diametrically opposed, the same key molecules are controlling pathology and, with differential targeting of therapeutics, may yet provide a beneficial outcome for both.
Collapse
Affiliation(s)
- Rachel M. Barker
- IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, Southmead Hospital, University of Bristol, Bristol, United Kingdom
| | - Jeff M. P. Holly
- IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, Southmead Hospital, University of Bristol, Bristol, United Kingdom
| | - Kalina M. Biernacka
- IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, Southmead Hospital, University of Bristol, Bristol, United Kingdom
| | - Shelley J. Allen-Birt
- Molecular Neurobiology Group, Bristol Medical School, Translational Health Sciences, Southmead Hospital, University of Bristol, Bristol, United Kingdom
| | - Claire M. Perks
- IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, Southmead Hospital, University of Bristol, Bristol, United Kingdom
| |
Collapse
|
|
30
|
Hopkins BD, Goncalves MD, Cantley LC. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol 2020; 16:276-283. [PMID: 32127696 PMCID: PMC7286536 DOI: 10.1038/s41574-020-0329-9] [Citation(s) in RCA: 174] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/30/2020] [Indexed: 12/17/2022]
Abstract
Cancer is driven by incremental changes that accumulate, eventually leading to oncogenic transformation. Although genetic alterations dominate the way cancer biologists think about oncogenesis, growing evidence suggests that systemic factors (for example, insulin, oestrogen and inflammatory cytokines) and their intracellular pathways activate oncogenic signals and contribute to targetable phenotypes. Systemic factors can have a critical role in both tumour initiation and therapeutic responses as increasingly targeted and personalized therapeutic regimens are used to treat patients with cancer. The endocrine system controls cell growth and metabolism by providing extracellular cues that integrate systemic nutrient status with cellular activities such as proliferation and survival via the production of metabolites and hormones such as insulin. When insulin binds to its receptor, it initiates a sequence of phosphorylation events that lead to activation of the catalytic activity of phosphoinositide 3-kinase (PI3K), a lipid kinase that coordinates the intake and utilization of glucose, and mTOR, a kinase downstream of PI3K that stimulates transcription and translation. When chronically activated, the PI3K pathway can drive malignant transformation. Here, we discuss the insulin-PI3K signalling cascade and emphasize its roles in normal cells (including coordinating cell metabolism and growth), highlighting the features of this network that make it ideal for co-option by cancer cells. Furthermore, we discuss how this signalling network can affect therapeutic responses and how novel metabolic-based strategies might enhance treatment efficacy for cancer.
Collapse
Affiliation(s)
- Benjamin D Hopkins
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Marcus D Goncalves
- Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
- Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Lewis C Cantley
- Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| |
Collapse
|
|
31
|
Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer's disease. Neurochem Int 2020; 135:104707. [PMID: 32092326 DOI: 10.1016/j.neuint.2020.104707] [Citation(s) in RCA: 160] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Its major pathological hallmarks, neurofibrillary tangles (NFT), and amyloid-β plaques can result from dysfunctional insulin signaling. Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function, autophagy, oxidative stress, synaptic plasticity, and cognitive function. Insulin and its downstream signaling molecules are located majorly in the regions of cortex and hippocampus. The major molecules involved in impaired insulin signaling include IRS, PI3K, Akt, and GSK-3β. Activation or inactivation of these major molecules through increased or decreased phosphorylation plays a role in insulin signaling abnormalities or insulin resistance. Insulin resistance, therefore, is considered as a major culprit in generating the hallmarks of AD arising from neuroinflammation and oxidative stress, etc. Moreover, caspases, Nrf2, and NF-κB influence this pathway in an indirect way. Various studies also suggest a strong link between Diabetes Mellitus and AD due to the impairment of insulin signaling pathway. Moreover, studies also depict a strong correlation of other neurodegenerative diseases such as Parkinson's disease and Huntington's disease with insulin resistance. Hence this review will provide an insight into the role of insulin signaling pathway and related molecules as therapeutic targets in AD and other neurodegenerative diseases.
Collapse
|
|
32
|
Li Z, Gao X, Peng X, May Chen MJ, Li Z, Wei B, Wen X, Wei B, Dong Y, Bu Z, Wu A, Wu Q, Tang L, Li Z, Liu Y, Zhang L, Jia S, Zhang L, Shan F, Zhang J, Wu X, Ji X, Ji K, Wu X, Shi J, Xing X, Wu J, Lv G, Shen L, Ji X, Liang H, Ji J. Multi-omics characterization of molecular features of gastric cancer correlated with response to neoadjuvant chemotherapy. SCIENCE ADVANCES 2020; 6:eaay4211. [PMID: 32133402 PMCID: PMC7043923 DOI: 10.1126/sciadv.aay4211] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 12/06/2019] [Indexed: 05/05/2023]
Abstract
Neoadjuvant chemotherapy is a common treatment for patients with gastric cancer. Although its benefits have been demonstrated, neoadjuvant chemotherapy is underutilized in gastric cancer management, because of the lack of biomarkers for patient selection and a limited understanding of resistance mechanisms. Here, we performed whole-genome, whole-exome, and RNA sequencing on 84 clinical samples (including matched pre- and posttreatment tumors) from 35 patients whose responses to neoadjuvant chemotherapy were rigorously defined. We observed increased microsatellite instability and mutation burden in nonresponse tumors. Through comparisons of response versus nonresponse tumors and pre- versus posttreatment samples, we found that C10orf71 mutations were associated with treatment resistance, which was supported by drug response data and potentially through inhibition of cell cycle, and that MYC amplification correlated with treatment sensitivity, whereas MDM2 amplification showed the opposite pattern. Neoadjuvant chemotherapy also reshapes tumor-immune signaling and microenvironment. Our study provides a critical basis for developing precision neoadjuvant regimens.
Collapse
Affiliation(s)
- Ziyu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiangyu Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xinxin Peng
- Precision Scientific (Beijing) Ltd., Beijing 100085, China
| | - Mei-Ju May Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhe Li
- Precision Scientific (Beijing) Ltd., Beijing 100085, China
| | - Bin Wei
- Precision Scientific (Beijing) Ltd., Beijing 100085, China
| | - Xianzi Wen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), GI Cancer Translation Research Lab, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Baoye Wei
- Precision Scientific (Beijing) Ltd., Beijing 100085, China
| | - Yu Dong
- Precision Scientific (Beijing) Ltd., Beijing 100085, China
| | - Zhaode Bu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Aiwen Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Qi Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Endoscopy Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Lei Tang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Zhongwu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yiqiang Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Li Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Shuqin Jia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular Diagnostics, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Lianhai Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Fei Shan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Ji Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiaojiang Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xin Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Ke Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiaolong Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jinyao Shi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), GI Cancer Translation Research Lab, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiaofang Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular Diagnostics, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jianmin Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Cancer Bioinformatics, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Guoqing Lv
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Lin Shen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of GI Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xuwo Ji
- Precision Scientific (Beijing) Ltd., Beijing 100085, China
| | - Han Liang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Corresponding author. (J.J.); (H.L.)
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
- Corresponding author. (J.J.); (H.L.)
| |
Collapse
|
|
33
|
Albegali AA, Shahzad M, Mahmood S, Ullah MI. Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population. Mol Biol Rep 2019; 46:6065-6070. [PMID: 31446532 DOI: 10.1007/s11033-019-05041-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 08/20/2019] [Indexed: 12/16/2022]
Abstract
Insulin resistance (IR), a pathological condition of type 2 diabetes mellitus (T2DM) is characterized by an inability of body's tissue to respond the secreted or administered insulin, a necessary step for cellular glucose transportation. The prevalence of insulin resistance progresses with age, especially in overweight people with central obesity. Insulin receptor substrates (IRS) are important molecular proteins in the insulin signalling pathway, where IRS-1 plays a key function in cells insulin sensitivity. The common mutation (rs1801278; r.2963G > A: Gly972Arg) of the IRS-1 gene occurs when residue glycine changes to arginine at codon 972. The objective of this study was to detect the genetic association of rs1801278 polymorphism of the IRS-1 gene with insulin resistance in type 2 diabetes from the Lahore region of Pakistan. A total of 322 subjects (161 cases and 161 healthy individuals) were included. DNA was isolated for detection of the genotype distribution and allele frequencies by PCR-RFLP. The results showed a significant difference in the genotype distribution and allele frequency between the T2DM cases and controls for single nucleotide polymorphism (SNP) rs1801278 (OR 17.61, 95% CI 8.06-38.4, p < 0.001). In conclusion, association between rs1801278 polymorphism of the IRS-1 gene and insulin resistance in T2DM has been established in a Pakistani population.
Collapse
Affiliation(s)
- Abdullah Abdo Albegali
- Department of Pharmacology, University of Health Sciences, Khayaban-e-Jamia Punjab Street, Lahore, 54600, Pakistan
| | - Muhammad Shahzad
- Department of Pharmacology, University of Health Sciences, Khayaban-e-Jamia Punjab Street, Lahore, 54600, Pakistan.
| | - Saqib Mahmood
- Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, 54600, Pakistan
| | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka, 2014, Kingdom of Saudi Arabia
| |
Collapse
|
|
34
|
You HL, Liu TT, Weng SW, Chen CH, Wei YC, Eng HL, Huang WT. Association of IRS2 overexpression with disease progression in intrahepatic cholangiocarcinoma. Oncol Lett 2018; 16:5505-5511. [PMID: 30250623 PMCID: PMC6144925 DOI: 10.3892/ol.2018.9284] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 07/27/2018] [Indexed: 12/19/2022] Open
Abstract
Insulin receptor substrate 2 (IRS2) is a candidate driver oncogene frequently amplified in cancer and is positively associated with IRS2 expression. The overexpression of IRS2 has been suggested to promote tumor metastasis. However, its function in intrahepatic cholangiocarcinoma (iCCA) has not been investigated extensively. The present study examined 86 cases of iCCA to analyze IRS2 expression and its correlation with clinicopathological characteristics using immunohistochemical assays. Three stable cell lines overexpressing IRS2 were established. The mobility potential of cells was compared in the basal condition and following manipulation using cell migration and invasion assays. Epithelial-mesenchymal transition (EMT)-associated proteins were assessed by western blotting. IRS2 was overexpressed in 29 iCCA cases (33.7%) and was significantly more frequent in cases with large tumor size (P=0.033), classified as an advanced stage by the American Joint Committee on Cancer (P=0.046). In comparison with the control cells, the three IRS2-overexpressing iCCA cell lines exhibited a statistically significant increase in mobility potential. Expression analysis of EMT markers demonstrated decreased epithelial marker levels and increased mesenchymal marker levels in IRS2-overexpressing cells compared with their corresponding control cells. The results of the present study indicate that IRS2 overexpression is characterized by a large tumor size and advanced tumor stage in iCCA, and that it may increase tumor mobility potential by regulating EMT pathways. Therefore, it is a valuable predictive indicator of metastasis and may provide a novel direction for targeted therapy in iCCA.
Collapse
Affiliation(s)
- Huey-Ling You
- Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, R.O.C
- Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 83102, Taiwan, R.O.C
| | - Ting-Ting Liu
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, R.O.C
| | - Shao-Wen Weng
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, R.O.C
| | - Chang-Han Chen
- The Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, R.O.C
| | - Yu-Ching Wei
- Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan, R.O.C
| | - Hock-Liew Eng
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, R.O.C
| | - Wan-Ting Huang
- Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, R.O.C
- Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 83102, Taiwan, R.O.C
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, R.O.C
| |
Collapse
|
|
35
|
Luo J, Feng J, Wen Q, Qoyawayma C, Wang W, Chen L, Lu J, Zhan Y, Xu L, Zang H, Fan S, Chu S. Elevated expression of IRS-1 associates with phosphorylated Akt expression and predicts poor prognosis of breast invasive ductal carcinoma. Hum Pathol 2018; 79:9-17. [DOI: 10.1016/j.humpath.2018.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 03/03/2018] [Accepted: 03/09/2018] [Indexed: 01/14/2023]
|
|
36
|
Janse van Rensburg HJ, Lai D, Azad T, Hao Y, Yang X. TAZ enhances mammary cell proliferation in 3D culture through transcriptional regulation of IRS1. Cell Signal 2018; 52:12-22. [PMID: 30138697 DOI: 10.1016/j.cellsig.2018.08.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/16/2018] [Accepted: 08/17/2018] [Indexed: 12/13/2022]
Abstract
WW domain-containing transcriptional regulator 1 (TAZ) is a transcriptional co-activator and effector of the Hippo signaling pathway. In certain breast cancer subtypes, Hippo signaling is dysregulated leading to activation of TAZ and altered expression of TAZ transcriptional targets. Over the past decade, we and others have found that TAZ transcriptionally regulates genes that affect multiple aspects of breast cancer cell behaviour. However, while cancer cell-intrinsic oncogenic functions of TAZ have emerged, less is known about whether TAZ might also contribute to tumourigenesis by sensitizing tumour cells to factors present in the tumour microenvironment or in systemic circulation. Here, we show that TAZ directly regulates the expression of insulin receptor substrate 1 (IRS1) in breast cancer cells. TAZ or IRS1 overexpression induces a similar proliferative transformation phenotype in MCF10A mammary epithelial cells. TAZ enhances IRS1 mRNA, protein levels and downstream signaling in MCF10A. Mechanistically, TAZ interacts with the IRS1 promoter through the TEAD family of transcription factors and enhances its activity. Critically, TAZ-induced IRS1 upregulation contributes to the proliferation of TAZ-overexpressing MCF10A in 3-dimensional (3D) Matrigel culture. Therefore, we offer compelling evidence that TAZ regulates signaling through the insulin pathway in breast cancer cells. These findings highlight an additional mechanism by which TAZ may promote breast cancer tumourigenesis and progression by modulating cancer cell responses to exogenously produced factors.
Collapse
Affiliation(s)
| | - Dulcie Lai
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | - Taha Azad
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | - Yawei Hao
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | - Xiaolong Yang
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada.
| |
Collapse
|
|
37
|
Insulin receptor substrate-4 is overexpressed in colorectal cancer and promotes retinoblastoma-cyclin-dependent kinase activation. J Gastroenterol 2018; 53:932-944. [PMID: 29353348 DOI: 10.1007/s00535-018-1432-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 01/12/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Insulin receptor substrate 4 (IRS-4) is an adaptor protein for which new evidence suggests plays a role in tumour promotion. METHODS We described nuclear IRS-4 in RKO colon cancer cell lines in biopsies of patients with colorectal cancer (CRC) (n = 20) and in matched adjacent normal colorectal (MANC) tissue (n = 20). RESULTS Treatment with physiological doses of IGF-1 promoted nuclear influx of IRS-4 from cellular cytosol in RKO cells. When exogenous IRS-4 was overexpressed in RKO cells, there was an increase in cyclin D1, cyclin E, E2F1, pRB Ser 809/811 and pRB Ser 705 levels compared with the empty vector-transfected cells. Some of these changes returned to control values after wortmannin treatment. Subcellular fractionation showed an overexpression of IRS-4 in the cytoplasm, membrane, and nuclei of tumour samples, whereas the levels of the protein were barely detectable in the three compartments of normal samples. Immunohistochemical studies showed positive nuclear IRS-4 staining in over 74% of the tumour cells. IRS-4 was strongly overexpressed in tumoural tissues from CRC patients compared to MANC tissues. The up-regulation of IRS-4 in CRC samples correlated significantly with the increase of several G1 checkpoint proteins including cyclin D1 (r = 0.6662), Rb (r = 0.7779), pRb Serine 809/811 (r = 0.6864), pRb serine 705 (r = 0.6261) and E2F1 (r = 0.8702). CONCLUSIONS Taken together, our findings suggest that IRS-4 promotes retinoblastoma-cyclin-dependent kinase activation and it may serve as a pharmacological target since its expression is very low in normal tissue, including colonic epithelium.
Collapse
|
|
38
|
Li X, Zhong L, Wang Z, Chen H, Liao D, Zhang R, Zhang H, Kang T. Phosphorylation of IRS4 by CK1γ2 promotes its degradation by CHIP through the ubiquitin/lysosome pathway. Am J Cancer Res 2018; 8:3643-3653. [PMID: 30026872 PMCID: PMC6037025 DOI: 10.7150/thno.26021] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 05/04/2018] [Indexed: 01/08/2023] Open
Abstract
IRS4, a member of the insulin receptor substrate protein family, can induce constitutive PI3K/AKT hyperactivation and cell proliferation even in the absence of insulin or growth factors and promote tumorigenesis, but its regulation has only been explored at the transcriptional level. Methods: Scansite was used to predict the potential protein kinases that may regulate the functions of IRS4, and mass spectrometry was used to identify the E3 ligase for IRS4. The protein interaction was carried out by immunoprecipitation, and protein stability was measured by cycloheximide treatment. In vitro kinase assay was used to determine the phosphorylation of IRS4 by casein kinase 1γ2 (CK1γ2). Colony formation assay and xenograft-bearing mice were employed to assess the cancer cell growth in vitro and in vivo, respectively. Immunohistochemistry was performed to examine protein levels of both IRS4 and CK1γ2 in osteosarcoma specimens and their relationship was evaluated by χ2 test. Two-tailed Student's t-test or the Mann-Whitney U test were used to compare the differences between subgroups. Results: IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). Using osteosarcoma cell lines, the ectopic nonphosphorylated mutant of IRS4 by CK1γ2 triggered higher level of p-Akt and displayed faster cell proliferation and cancer growth in vitro and in nude mice. In addition, a negative correlation in protein levels between CK1γ2 and IRS4 was observed in osteosarcoma cell lines and tissue samples. Conclusions: IRS4, as a new substrate of CHIP, is negatively regulated by CK1γ2 at the posttranslational level, and specific CK1γ2 agonists may be a potentially effective strategy for treating patients with osteosarcoma.
Collapse
|
|
39
|
Khalid S, Hanif R, Jabeen I, Mansoor Q, Ismail M. Pharmacophore modeling for identification of anti-IGF-1R drugs and in-vitro validation of fulvestrant as a potential inhibitor. PLoS One 2018; 13:e0196312. [PMID: 29787591 PMCID: PMC5963753 DOI: 10.1371/journal.pone.0196312] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 04/10/2018] [Indexed: 01/10/2023] Open
Abstract
Insulin-like growth factor 1 receptor (IGF-1R) is an important therapeutic target for breast cancer treatment. The alteration in the IGF-1R associated signaling network due to various genetic and environmental factors leads the system towards metastasis. The pharmacophore modeling and logical approaches have been applied to analyze the behaviour of complex regulatory network involved in breast cancer. A total of 23 inhibitors were selected to generate ligand based pharmacophore using the tool, Molecular Operating Environment (MOE). The best model consisted of three pharmacophore features: aromatic hydrophobic (HyD/Aro), hydrophobic (HyD) and hydrogen bond acceptor (HBA). This model was validated against World drug bank (WDB) database screening to identify 189 hits with the required pharmacophore features and was further screened by using Lipinski positive compounds. Finally, the most effective drug, fulvestrant, was selected. Fulvestrant is a selective estrogen receptor down regulator (SERD). This inhibitor was further studied by using both in-silico and in-vitro approaches that showed the targeted effect of fulvestrant in ER+ MCF-7 cells. Results suggested that fulvestrant has selective cytotoxic effect and a dose dependent response on IRS-1, IGF-1R, PDZK1 and ER-α in MCF-7 cells. PDZK1 can be an important inhibitory target using fulvestrant because it directly regulates IGF-1R.
Collapse
Affiliation(s)
- Samra Khalid
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
- Northern Institute for Cancer Research, Newcastle upon Tyne Hospitals NHS Foundation Trust, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
| | - Rumeza Hanif
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
- * E-mail:
| | - Ishrat Jabeen
- Research Center for Modeling & Simulation (RCMS), National University of Sciences and Technology, Islamabad, Pakistan
| | - Qaisar Mansoor
- Institute of Biomedical and Genetic Engineering (IBGE), KRL Hospital, Islamabad, Pakistan
| | - Muhammad Ismail
- Institute of Biomedical and Genetic Engineering (IBGE), KRL Hospital, Islamabad, Pakistan
| |
Collapse
|
|
40
|
Jeon SH, Yoo JK, Kim CM, Lim ES, Lee SJ, Lee JM, Oh SH, Kim JK. The novel hsa-miR-12528 regulates tumourigenesis and metastasis through hypo-phosphorylation of AKT cascade by targeting IGF-1R in human lung cancer. Cell Death Dis 2018; 9:493. [PMID: 29712908 PMCID: PMC5928042 DOI: 10.1038/s41419-018-0535-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 01/31/2018] [Accepted: 02/19/2018] [Indexed: 01/01/2023]
Abstract
Lung cancer cases are increasing yearly; however, few novel therapeutic strategies for treating this disease have been developed. Here the dysregulation between microRNAs and oncogenes or tumour-suppressor genes forms a close connection-loop to the development or progression in human lung carcinogenesis. That is, the relationship between microRNAs and carcinogenic mechanism may find the critical clue to improve the treatment efficacy. Accordingly, we identified and characterised a novel microRNA, hsa-miR-12528, in A549 cells. The miR-12528 expression was aberrantly downregulated in cancer cell lines and in the patient tissues derived from human non-small cell lung cancer. In addition, we found that miR-12528 post-transcriptionally controls the translation of the insulin-like growth factor 1 receptor (IGF-1R) gene by directly targeting the 3′-untranslated region of IGF-1R mRNA. Notably, the IGF-1R gene is elevated in the majority of cancers and may be an attractive therapeutic target for anticancer therapy because elevated IGF-1R mediates the signalling amplification of a major oncogenic pathway in neoplasia. In A549 cells, miR-12528 overexpression epigenetically altered the downstream phosphorylation of the primary IGF-1R networks, negatively regulated proliferation, apoptosis and migratory activity, and consequently inhibited tumourigenesis and metastasis in vivo. Therefore, our discovery of hsa-miR-12528 may be able to be applied to the development of molecular-target therapeutic strategies and diagnosis-specific biomarkers for human lung cancer.
Collapse
Affiliation(s)
- Seong Ho Jeon
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - Jung Ki Yoo
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - Chang Min Kim
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - Eun Su Lim
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - So Jeong Lee
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - Ji Min Lee
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.,Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 463-954, Republic of Korea
| | - Seung-Hun Oh
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 463-954, Republic of Korea
| | - Jin Kyeoung Kim
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
| |
Collapse
|
|
41
|
Yin J, Zhang Z, Zheng H, Xu L. IRS-2 rs1805097 polymorphism is associated with the decreased risk of colorectal cancer. Oncotarget 2018; 8:25107-25114. [PMID: 28212577 PMCID: PMC5421913 DOI: 10.18632/oncotarget.15342] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 01/27/2017] [Indexed: 01/11/2023] Open
Abstract
Recent studies explored the association between insulin receptor substrate-2 (IRS-2) gene rs1805097 polymorphism and colorectal cancer (CRC) with contradictory findings. Therefore, we conducted a comprehensive meta-analysis by searching the databases of PubMed and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using fixed-effect or random-effect models. A total of 5 citations containing 6 case-control studies involving 4,333 cases and 5,333 controls were included. Our data indicated that IRS-2 rs1805097 polymorphism was associated with decreased risk of CRC. Stratification analysis of ethnicity found that rs1805097 polymorphism decreased the risk of CRC among Americans. Stratification analysis of cancer type suggested that this polymorphism decreased the risk of colon cancer. In summary, this meta-analysis indicates that IRS-2 gene rs1805097 polymorphism plays an important role in the pathogenesis of CRC.
Collapse
Affiliation(s)
- Jiefeng Yin
- General Surgery Department, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhe Zhang
- General Surgery Department, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Huajun Zheng
- Department of Digestion, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Lei Xu
- Department of Digestion, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| |
Collapse
|
|
42
|
Wang S, Cheng Y, Gao Y, He Z, Zhou W, Chang R, Peng Z, Zheng Y, Duan C, Zhang C. SH2B1 promotes epithelial-mesenchymal transition through the IRS1/β-catenin signaling axis in lung adenocarcinoma. Mol Carcinog 2018; 57:640-652. [PMID: 29380446 PMCID: PMC5900930 DOI: 10.1002/mc.22788] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Revised: 11/13/2017] [Accepted: 01/24/2018] [Indexed: 12/11/2022]
Abstract
Lung adenocarcinoma (LADC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2‐domain containing family, have recently been shown to act as tumor activators in multiple cancers, including LADC. However, the mechanisms underlying SH2B1 overexpression are not completely understood. Here, we reported that SH2B1 expression levels were significantly upregulated and positively associated with EMT markers and poor patient survival in LADC specimens. Modulation of SH2B1 levels had distinct effects on cell proliferation, cell cycle, migration, invasion, and morphology in A549 and H1299 cells in vitro and in vivo. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the EMT markers, especially induced β‐catenin accumulation and activated β‐catenin signaling to promote LADC cell proliferation and metastasis, while silencing SH2B1 had the opposite effect. Furthermore, ectopic expression of SH2B1 in H1299 cells increased IRS1 expression level. Reduced expression of IRS1 considerably inhibited H1299 cell proliferation, migration, and invasion which were driven by SH2B1 overexpression. Collectively, these results provide unequivocal evidence to establish that SH2B1‐IRS1‐β‐catenin axis is required for promoting EMT, and might prove to be a promising strategy for restraining tumor progression in LADC patients.
Collapse
Affiliation(s)
- Shaoqiang Wang
- Department of Thoracic Surgery, Affiliated Hospital of Jining Medical College, Jining Medical College, Jining, Shandong, P.R. China
| | - Yuanda Cheng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Yang Gao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Zhiwei He
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Wolong Zhou
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Ruimin Chang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Zhenzi Peng
- Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Yingying Zheng
- Department of Endocrinology, Affiliated Hospital of Jining Medical College, Jining Medical College, Jining, Shandong, P.R. China
| | - Chaojun Duan
- Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| |
Collapse
|
|
43
|
Down-regulation of tensin2 enhances tumorigenicity and is associated with a variety of cancers. Oncotarget 2018; 7:38143-38153. [PMID: 27203214 PMCID: PMC5122378 DOI: 10.18632/oncotarget.9411] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 04/28/2016] [Indexed: 12/27/2022] Open
Abstract
Tensin family members, including tensin2 (TNS2), are present as major components of the focal adhesions. The N-terminal end of TNS2 contains a C1 region (protein kinase C conserved region 1) that is not found in other tensin members. Three isoforms of TNS2 have been identified with previous reports describing the shortest V3 isoform as lacking the C1 region. Although TNS2 is known to regulate cell proliferation and migration, its role in tumorigenicity is controversial. By gain-of-function overexpression approaches, results supporting either promotion or reduction of cancer cell tumorigenicity were reported. Here we report that the complete V3 isoform also contains the C1 region and describe the expression patterns of the three human TNS2 isoforms. By loss-of-function approaches, we show that silencing of TNS2 up-regulates the activities of Akt, Mek, and IRS1, and increases tumorigenicities in A549 and Hela cells. Using public database analyses we found that TNS2 is down-regulated in head and neck, esophageal, breast, lung, liver, and colon cancer. In addition, patients with low TNS2 expression showed poor relapse-free survival rates for breast and lung cancers. These results strongly suggest a role of tensin2 in suppressing cell transformation and reduction of tumorigenicity.
Collapse
|
|
44
|
Kumar AS, Rayala SK, Venkatraman G. Targeting IGF1R pathway in cancer with microRNAs: How close are we? RNA Biol 2018; 15:320-326. [PMID: 28613101 DOI: 10.1080/15476286.2017.1338240] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cancer of the head and neck are the most common cancers in India and account for 30% of all cancers. At molecular level, it could be attributed to the overexpression of growth factors like IGF1-R, EGFR, VEGF-R and deregulation of cell cycle regulators and tumor suppressors. IGF1-R is an emerging target in head and neck cancer treatment, because of its reported role in tumor development, progression and metastasis. IGF1R targeted agents are in advanced stages of clinical development. Nevertheless, these agents suffer from several disadvantages including acquired resistance and toxic side effects. Hence there is a need for developing newer agents targeting not only the receptor but also its downstream signaling. miRNAs are considered as master regulators of gene expression of multiple genes and has been widely reported to be a promising therapeutic strategy. This review discusses the present status of research in both these arenas and emphasizes the role of miRNA as a promising agent for biologic therapy.
Collapse
Affiliation(s)
- Arathy S Kumar
- a Department of Biotechnology , Indian Institute of Technology, Madras (IIT M) , Chennai , India
| | - Suresh K Rayala
- a Department of Biotechnology , Indian Institute of Technology, Madras (IIT M) , Chennai , India
| | - Ganesh Venkatraman
- b Department of Human Genetics , College of Biomedical Sciences, Technology & Research, Sri Ramachandra University , Porur, Chennai , India
| |
Collapse
|
|
45
|
Wang G, Pan J, Zhang L, Wei Y, Wang C. Long non-coding RNA CRNDE sponges miR-384 to promote proliferation and metastasis of pancreatic cancer cells through upregulating IRS1. Cell Prolif 2017; 50:e12389. [PMID: 28940804 PMCID: PMC6529119 DOI: 10.1111/cpr.12389] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 09/03/2017] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Colorectal neoplasia differentially expressed (CRNDE), a vital cancer-related long non-coding RNA (lncRNA), has been brought to reports for playing quintessential functions in the growth and progression of several human malignancies. Nevertheless, the expression as well as the functional mechanisms of CRNDE in pancreatic cancer is not known so for. This study aimed at investigating the biological and clinical importance of CRNDE in human pancreatic cancer. MATERIALS AND METHODS The expression levels of CRNDE in pancreatic cancer tissues as well as cell lines were identified with the help of quantitative real-time PCR (qRT-PCR). Furthermore, the analysis of the relationship between CRNDE expression and clinicopathologic characteristics of patients with pancreatic cancer was also performed. Novel target of CRNDE was identified with the use of bioinformatics analysis and confirmed by a dual-luciferase reporter assay. Colorectal neoplasia differentially expressed was knocked down using siRNA in pancreatic cancer cells. Thereafter, cell proliferation, migration and invasion were examined. Tumour xenograft was created to explore the function of CRNDE in tumorigenesis in vivo. RESULTS Upregulation of the expression of CRNDE was found in pancreatic cancer tissues as well as cell lines, in comparison with the adjacent non-tumour tissues and human pancreatic duct epithelial cells. High expression of CRNDE was correlated with poor clinicpathological characteristics and shorter overall survival. We identified miR-384 as a direct target for CRNDE. Moreover, the CRNDE knockdown considerably inhibited pancreatic cancer cell proliferation, migration and invasion not only in vitro but also in vivo. In addition, CRNDE positively regulated IRS1 expression through sponging miR-384. CONCLUSIONS Colorectal neoplasia differentially expressed performed an oncogenic function in cell proliferation as well as metastasis of pancreatic cancer. Our results suggest that CRNDE is likely to serve as an efficient therapeutic approach in respect of pancreatic cancer treatment.
Collapse
Affiliation(s)
- Gang Wang
- Department of Biliary and Pancreatic SurgeryAnhui Provincial Hospital Affiliated with Anhui Medical UniversityHefeiAnhuiChina
| | - Jingen Pan
- Department of Biliary and Pancreatic SurgeryAnhui Provincial Hospital Affiliated with Anhui Medical UniversityHefeiAnhuiChina
| | - Lu Zhang
- Department of Biliary and Pancreatic SurgeryAnhui Provincial Hospital Affiliated with Anhui Medical UniversityHefeiAnhuiChina
| | - Yajun Wei
- Department of Biliary and Pancreatic SurgeryAnhui Provincial Hospital Affiliated with Anhui Medical UniversityHefeiAnhuiChina
| | - Cheng Wang
- Department of Biliary and Pancreatic SurgeryAnhui Provincial Hospital Affiliated with Anhui Medical UniversityHefeiAnhuiChina
| |
Collapse
|
|
46
|
Overexpression of insulin receptor substrate-4 is correlated with clinical staging in colorectal cancer patients. J Mol Histol 2017; 49:39-49. [DOI: 10.1007/s10735-017-9745-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 11/23/2017] [Indexed: 01/05/2023]
|
|
47
|
Yuan J, Yin Z, Tao K, Wang G, Gao J. Function of insulin-like growth factor 1 receptor in cancer resistance to chemotherapy. Oncol Lett 2017; 15:41-47. [PMID: 29285186 DOI: 10.3892/ol.2017.7276] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 09/28/2017] [Indexed: 02/07/2023] Open
Abstract
Drug resistance is a primary cause of chemotherapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin-like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R-induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP-binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options.
Collapse
Affiliation(s)
- Jingsheng Yuan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Zhijie Yin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Guobing Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jinbo Gao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| |
Collapse
|
|
48
|
A Comprehensive Survey of the Roles of Highly Disordered Proteins in Type 2 Diabetes. Int J Mol Sci 2017; 18:ijms18102010. [PMID: 28934129 PMCID: PMC5666700 DOI: 10.3390/ijms18102010] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 09/04/2017] [Accepted: 09/12/2017] [Indexed: 01/03/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with hyperglycemia (high blood sugar) related to either insulin resistance or insufficient insulin production. Among the various molecular events and players implicated in the manifestation and development of diabetes mellitus, proteins play several important roles. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database has information on 34 human proteins experimentally shown to be related to the T2DM pathogenesis. It is known that many proteins associated with different human maladies are intrinsically disordered as a whole, or contain intrinsically disordered regions. The presented study shows that T2DM is not an exception to this rule, and many proteins known to be associated with pathogenesis of this malady are intrinsically disordered. The multiparametric bioinformatics analysis utilizing several computational tools for the intrinsic disorder characterization revealed that IRS1, IRS2, IRS4, MAFA, PDX1, ADIPO, PIK3R2, PIK3R5, SoCS1, and SoCS3 are expected to be highly disordered, whereas VDCC, SoCS2, SoCS4, JNK9, PRKCZ, PRKCE, insulin, GCK, JNK8, JNK10, PYK, INSR, TNF-α, MAPK3, and Kir6.2 are classified as moderately disordered proteins, and GLUT2, GLUT4, mTOR, SUR1, MAPK1, IKKA, PRKCD, PIK3CB, and PIK3CA are predicted as mostly ordered. More focused computational analyses and intensive literature mining were conducted for a set of highly disordered proteins related to T2DM. The resulting work represents a comprehensive survey describing the major biological functions of these proteins and functional roles of their intrinsically disordered regions, which are frequently engaged in protein–protein interactions, and contain sites of various posttranslational modifications (PTMs). It is also shown that intrinsic disorder-associated PTMs may play important roles in controlling the functions of these proteins. Consideration of the T2DM proteins from the perspective of intrinsic disorder provides useful information that can potentially lead to future experimental studies that may uncover latent and novel pathways associated with the disease.
Collapse
|
|
49
|
Zhang XF, Ou-Yang L, Yan H. Node-based differential network analysis in genomics. Comput Biol Chem 2017; 69:194-201. [DOI: 10.1016/j.compbiolchem.2017.03.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 03/27/2017] [Indexed: 12/26/2022]
|
|
50
|
Ou-Yang L, Yan H, Zhang XF. Identifying differential networks based on multi-platform gene expression data. MOLECULAR BIOSYSTEMS 2017; 13:183-192. [PMID: 27868129 DOI: 10.1039/c6mb00619a] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Exploring how the structure of a gene regulatory network differs between two different disease states is fundamental for understanding the biological mechanisms behind disease development and progression. Recently, with rapid advances in microarray technologies, gene expression profiles of the same patients can be collected from multiple microarray platforms. However, previous differential network analysis methods were usually developed based on a single type of platform, which could not utilize the common information shared across different platforms. In this study, we introduce a multi-view differential network analysis model to infer the differential network between two different patient groups based on gene expression profiles collected from multiple platforms. Unlike previous differential network analysis models that need to analyze each platform separately, our model can draw support from multiple data platforms to jointly estimate the differential networks and produce more accurate and reliable results. Our simulation studies demonstrate that our method consistently outperforms other available differential network analysis methods. We also applied our method to identify network rewiring associated with platinum resistance using TCGA ovarian cancer samples. The experimental results demonstrate that the hub genes in our identified differential networks on the PI3K/AKT/mTOR pathway play an important role in drug resistance.
Collapse
Affiliation(s)
- Le Ou-Yang
- College of Information Engineering, Shenzhen University, Shenzhen, China and Department of Electronic and Engineering, City University of Hong Kong, Hong Kong, China
| | - Hong Yan
- Department of Electronic and Engineering, City University of Hong Kong, Hong Kong, China
| | - Xiao-Fei Zhang
- School of Mathematics and Statistics & Hubei Key Laboratory of Mathematical Sciences, Central China Normal University, Wuhan, China.
| |
Collapse
|