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Stefàno E, De Castro F, Ciccarese A, Muscella A, Marsigliante S, Benedetti M, Fanizzi FP. An Overview of Altered Pathways Associated with Sensitivity to Platinum-Based Chemotherapy in Neuroendocrine Tumors: Strengths and Prospects. Int J Mol Sci 2024; 25:8568. [PMID: 39201255 PMCID: PMC11354135 DOI: 10.3390/ijms25168568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/30/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.
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Affiliation(s)
| | | | | | | | | | - Michele Benedetti
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Monteroni, I-73100 Lecce, Italy; (E.S.); (F.D.C.); (A.C.); (A.M.); (S.M.); (F.P.F.)
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2
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Zhao W, Huang R, Ran D, Zhang Y, Qu Z, Zheng S. Inhibiting HSD17B8 suppresses the cell proliferation caused by PTEN failure. Sci Rep 2024; 14:12280. [PMID: 38811827 PMCID: PMC11137105 DOI: 10.1038/s41598-024-63052-5] [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] [Academic Contribution Register] [Received: 01/31/2024] [Accepted: 05/24/2024] [Indexed: 05/31/2024] Open
Abstract
Loss of the tumor suppressor PTEN homolog daf-18 in Caenorhabditis elegans (C. elegans) triggers diapause cell division during L1 arrest. While prior studies have delved into established pathways, our investigation takes an innovative route. Through forward genetic screening in C. elegans, we pinpoint a new player, F12E12.11, regulated by daf-18, impacting cell proliferation independently of PTEN's typical phosphatase activity. F12E12.11 is an ortholog of human estradiol 17-beta-dehydrogenase 8 (HSD17B8), which converts estradiol to estrone through its NAD-dependent 17-beta-hydroxysteroid dehydrogenase activity. We found that PTEN engages in a physical interplay with HSD17B8, introducing a distinctive suppression mechanism. The reduction in estrone levels and accumulation of estradiol may arrest tumor cells in the G2/M phase of the cell cycle through MAPK/ERK. Our study illuminates an unconventional protein interplay, providing insights into how PTEN modulates tumor suppression by restraining cell division through intricate molecular interactions.
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Affiliation(s)
- Wei Zhao
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan Province, China
- Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Medical School of Henan University, Kaifeng, Henan Province, China
| | - Ruiting Huang
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan Province, China
| | - Dongyang Ran
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan Province, China
| | - Yutong Zhang
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan Province, China
| | - Zhi Qu
- School of Nursing and Health, Henan University, Kaifeng, Henan Province, China.
| | - Shanqing Zheng
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan Province, China.
- Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Medical School of Henan University, Kaifeng, Henan Province, China.
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Marcon F, Giunta S, Bignami M. Emerging roles of DNA repair factors in the stability of centromeres. Semin Cell Dev Biol 2024; 156:121-129. [PMID: 37852903 DOI: 10.1016/j.semcdb.2023.10.001] [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] [Academic Contribution Register] [Received: 06/09/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/20/2023]
Abstract
Satellite DNA sequences are an integral part of centromeres, regions critical for faithful segregation of chromosomes during cell division. Because of their complex repetitive structure, satellite DNA may act as a barrier to DNA replication and other DNA based transactions ultimately resulting in chromosome breakage. Over the past two decades, several DNA repair proteins have been shown to bind and function at centromeres. While the importance of these repair factors is highlighted by various structural and numerical chromosome aberrations resulting from their inactivation, their roles in helping to maintain genome stability by solving the intrinsic difficulties of satellite DNA replication or promoting their repair are just starting to emerge. In this review, we summarize the current knowledge on the role of DNA repair and DNA damage response proteins in maintaining the structure and function of centromeres in different contexts. We also report the recent connection between the roles of specific DNA repair factors at these genomic loci with age-related increase of chromosomal instability under physiological and pathological conditions.
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Affiliation(s)
- Francesca Marcon
- Department of Environment and Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
| | - Simona Giunta
- Laboratory of Genome Evolution, Department of Biology and Biotechnologies Charles Darwin, Sapienza University of Rome, 00185, Italy
| | - Margherita Bignami
- Department of Environment and Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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Hitomi M, Venegas J, Kang SC, Eng C. Differential cell cycle checkpoint evasion by PTEN germline mutations associated with dichotomous phenotypes of cancer versus autism spectrum disorder. Oncogene 2023; 42:3698-3707. [PMID: 37907589 DOI: 10.1038/s41388-023-02867-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/29/2023] [Revised: 09/29/2023] [Accepted: 10/10/2023] [Indexed: 11/02/2023]
Abstract
Individuals with a PTEN germline mutation receive the molecular diagnosis of PTEN hamartoma tumor syndrome (PHTS). PHTS displays a complex spectrum of clinical phenotypes including harmartomas, predisposition to cancers, and autism spectrum disorder (ASD). Clear-cut genotype-phenotype correlations are yet to be established due to insufficient information on the PTEN function being impacted by mutations. To fill this knowledge gap, we compared functional impacts of two selected missense PTEN mutant alleles, G132D and M134R, each respectively being associated with distinct clinical phenotype, ASD or thyroid cancer without ASD using gene-edited human induced pluripotent stem cells (hiPSCs). In homozygous hiPSCs, PTEN expression was severely reduced by M134R mutation due to shortened protein half-life. G132D suppressed PTEN expression to a lesser extent than Μ134R mutation without altering protein half-life. When challenged with γ-irradiation, G132D heterozygous cells exited radiation-induced G2 arrest earlier than wildtype and M134R heterozygous hiPSCs despite the similar DNA damage levels as the latter two. Immunoblotting analyses suggested that γ-irradiation induced apoptosis in G132D heterozygous cells to lesser degrees than in the hiPSCs of other genotypes. These data suggest that ASD-associated G132D allele promotes genome instability by premature cell cycle reentry with incomplete DNA repair.
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Affiliation(s)
- Masahiro Hitomi
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
- Department of Molecular Medicine, The Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA
| | - Juan Venegas
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Shin Chung Kang
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
- Department of Molecular Medicine, The Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA.
- Center for Personalized Genetic Healthcare, Medical Specialties Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
- Department of Genetics and Genome Science, Case Western Reserve University School of Medicine, Cleveland, OH, 44116, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44116, USA.
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Zhao JL, Yang J, Li K, Chen Y, Tang M, Zhu HL, Nie CL, Yuan Z, Zhao XY. Abrogation of ATR function preferentially augments cisplatin-induced cytotoxicity in PTEN-deficient breast cancer cells. Chem Biol Interact 2023; 385:110740. [PMID: 37802411 DOI: 10.1016/j.cbi.2023.110740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/08/2023] [Revised: 09/07/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
Targeting replication stress response is currently emerging as new therapeutic strategy for cancer treatment, based on monotherapy and combination approaches. As a key sensor in response to DNA damage, ataxia telangiectasia and rad3-related (ATR) kinase has become a potential therapeutic target as tumor cells are to rely heavily on ATR for survival. The tumor suppressor phosphatase and tensin homolog (PTEN) plays a crucial role in maintaining chromosome integrity. Although ATR inhibition was recently confirmed to show a synergistic inhibitory effect in PTEN-deficient triple-negative breast cancer cells, the molecular mechanism needs to be further elucidated. Additionally, whether the PTEN-deficient breast cancer cells are more preferentially sensitized than PTEN-wild type breast cancer cells to cisplatin plus ATR inhibitor remains unanswered. We demonstrate PTEN dysfunction promotes the killing effect of ATR blockade through the use of RNA interference for PTEN and a highly selective ATR inhibitor VE-821, and certify that VE-821 (1.0 μmol/L) aggravates cytotoxicity of cisplatin on breast cancer cells, especially PTEN-null MDA-MB-468 cells which show more chemoresistance than PTEN-expressing MDA-MB-231 cells. The co-treatment with VE-821 and cisplatin significantly reduced cell viability and proliferative capacity compared with cisplatin mono-treatment (P < 0.05). The increased cytotoxic activity is tied to the enhanced poly (ADP-ribose) polymerase (PARP) cleavage and consequently cell death due to the decrease in phosphorylation levels of checkpoint kinases 1 and 2 (CHK1/2), the reduction of radiation sensitive 51 (RAD51) foci and the increase in phosphorylation of the histone variant H2AX (γ-H2AX) foci (P < 0.05) as well. Together, these findings suggest combination therapy of ATR inhibitor and cisplatin may offer a potential therapeutic strategy for breast tumors.
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Affiliation(s)
- Jian-Lei Zhao
- Department of Pharmacology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Jun Yang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ke Li
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yang Chen
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mei Tang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hui-Li Zhu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Chun-Lai Nie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhu Yuan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xin-Yu Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Ertay A, Ewing RM, Wang Y. Synthetic lethal approaches to target cancers with loss of PTEN function. Genes Dis 2023; 10:2511-2527. [PMID: 37533462 PMCID: PMC7614861 DOI: 10.1016/j.gendis.2022.12.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/16/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 02/05/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene and has a role in inhibiting the oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumour phenotype and tumorigenesis. Identifying targeted therapies for inactive tumour suppressor genes such as PTEN has been challenging as it is difficult to restore the tumour suppressor functions. Therefore, focusing on the downstream signalling pathways to discover a targeted therapy for inactive tumour suppressor genes has highlighted the importance of synthetic lethality studies. This review focuses on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.
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Affiliation(s)
- Ayse Ertay
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Rob M. Ewing
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Yihua Wang
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
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Torres-Montaner A. Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis. Curr Issues Mol Biol 2023; 45:7582-7616. [PMID: 37754262 PMCID: PMC10527771 DOI: 10.3390/cimb45090478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/02/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 09/28/2023] Open
Abstract
Contrary to what was once thought, direct cancer originating from normal stem cells seems to be extremely rare. This is consistent with a preneoplastic period of telomere length reduction/damage in committed cells that becomes stabilized in transformation. Multiple observations suggest that telomere damage is an obligatory step preceding its stabilization. During tissue turnover, the telomeres of cells undergoing differentiation can be damaged as a consequence of defective DNA repair caused by endogenous or exogenous agents. This may result in the emergence of new mechanism of telomere maintenance which is the final outcome of DNA damage and the initial signal that triggers malignant transformation. Instead, transformation of stem cells is directly induced by primary derangement of telomere maintenance mechanisms. The newly modified telomere complex may promote survival of cancer stem cells, independently of telomere maintenance. An inherent resistance of stem cells to transformation may be linked to specific, robust mechanisms that help maintain telomere integrity.
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Affiliation(s)
- Antonio Torres-Montaner
- Department of Pathology, Queen’s Hospital, Rom Valley Way, Romford, London RM7 OAG, UK;
- Departamento de Bioquímica y Biologia Molecular, Universidad de Cadiz, Puerto Real, 11510 Cadiz, Spain
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Ghosh G, Misra S, Ray R, Chowdhury SG, Karmakar P. Phospho PTEN mediated dephosphorylation of mitotic kinase PLK1 and Aurora Kinase A prevents aneuploidy and preserves genomic stability. Med Oncol 2023; 40:119. [PMID: 36930246 DOI: 10.1007/s12032-023-01985-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/19/2023] [Accepted: 02/23/2023] [Indexed: 03/18/2023]
Abstract
PTEN, dual phosphatase tumor suppressor protein, is found to be frequently mutated in various cancers. Post-translational modification of PTEN is important for its sub-cellular localization and catalytic functions. But how these modifications affect cytological damage and aneuploidy is not studied in detail. We focus on the role of phosphatase activity along with C-terminal phosphorylation of PTEN in perspective of cytological damage like micronucleus, nuclear bud, and nuclear bridge formation. Our data suggest that wild-type PTEN, but not phospho-mutant PTEN significantly reduces cytological damage in PTEN null PC3 cells. In case of phosphatase-dead PTEN, cytological damage markers are increased during 24 h recovery after DNA damage. When we use phosphorylation and phosphatase-dead dual mutant PTEN, the extent of different cytological DNA damage parameters are similar to phosphatase-dead PTEN. We also find that both of those activities are essential for maintaining chromosome numbers. PTEN null cells exhibit significantly aberrant γ-tubulin pole formation during metaphase. Interestingly, we observed that p-PTEN localized to spindle poles along with PLK1 and Aurora Kinase A. Further depletion of phosphorylation and phosphatase activity of PTEN increases the expression of p-Aurora Kinase A (T288) and p-PLK1 (T210), compared to cells expressing wild-type PTEN. Again, wild-type PTEN but not phosphorylation-dead mutant is able to physically interact with PLK1 and Aurora Kinase A. Thus, our study suggests that the phosphorylation-dependent interaction of PTEN with PLK1 and Aurora Kinase A causes dephosphorylation of those mitotic kinases and by lowering their hyperphosphorylation status, PTEN prevents aberrant chromosome segregation in metaphase.
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Affiliation(s)
- Ginia Ghosh
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, West Bengal, India
| | - Sandip Misra
- Department of Microbiology, Bidhannagar College, Salt Lake, Kolkata, West Bengal, India
| | - Rachayeeta Ray
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, West Bengal, India
| | - Sougata Ghosh Chowdhury
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, West Bengal, India
| | - Parimal Karmakar
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, West Bengal, India.
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Dong L, Li Y, Liu L, Meng X, Li S, Han D, Xiao Z, Xia Q. Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation. Cells 2022; 11:3302. [PMID: 36291166 PMCID: PMC9600526 DOI: 10.3390/cells11203302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/30/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
The tumor suppressor PTEN mainly inhibits the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus. The status of PTEN remains therapeutic effectiveness for chemoresistance of the DNA alkylating agent temozolomide (TMZ) in glioblastoma (GB). However, the underlying mechanisms of PTEN's interconnected role in the cytoplasm and nucleus in TMZ resistance are still unclear. In this study, we report that TMZ-induced PTEN nuclear import depends on PTEN ubiquitylation modification by Smurf1. The Smurf1 suppression decreases the TMZ-induced PTEN nuclear translocation and enhances the DNA damage. In addition, Smurf1 degrades cytoplasmic PTEN K289E (the nuclear-import-deficient PTEN mutant) to activate the PI3K/Akt pathway under TMZ treatment. Altogether, Smurf1 interconnectedly promotes PTEN nuclear function (DNA repair) and cytoplasmic function (activation of PI3K/Akt pathway) to resist TMZ. These results provide a proof-of-concept demonstration for a potential strategy to overcome the TMZ resistance in PTEN wild-type GB patients by targeting Smurf1.
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Affiliation(s)
| | | | | | | | | | | | | | - Qin Xia
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
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Abstract
ABSTRACT The phosphosphatidylinositol-3-kinase (PI3K) signaling pathway is one of the most important intracellular signal transduction pathways affecting cell functions, such as apoptosis, translation, metabolism, and angiogenesis. Lung cancer is a malignant tumor with the highest morbidity and mortality rates in the world. It can be divided into two groups, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for >85% of all lung cancers. There are currently many clinical treatment options for NSCLC; however, traditional methods such as surgery, chemotherapy, and radiotherapy have not been able to provide patients with good survival benefits. The emergence of molecular target therapy has improved the survival and prognosis of patients with NSCLC. In recent years, there have been an increasing number of studies on NSCLC and PI3K signaling pathways. Inhibitors of various parts of the PI3K pathway have appeared in various phases of clinical trials with NSCLC as an indication. This article focuses on the role of the PI3K signaling pathway in the occurrence and development of NSCLC and summarizes the current clinical research progress and possible development strategies.
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Misra S, Chowdhury SG, Ghosh G, Mukherjee A, Karmakar P. Both phosphorylation and phosphatase activity of PTEN are required to prevent replication fork progression during stress by inducing heterochromatin. Mutat Res 2022; 825:111800. [PMID: 36155262 DOI: 10.1016/j.mrfmmm.2022.111800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/15/2022] [Revised: 08/26/2022] [Accepted: 09/09/2022] [Indexed: 06/16/2023]
Abstract
PTEN is a tumor suppressor protein frequently altered in various cancers. PTEN-null cells have a characteristic of rapid proliferation with an unstable genome. Replication stress is one of the causes of the accumulation of genomic instability if not sensed by the cellular signaling. Though PTEN-null cells have shown to be impaired in replication progression and stalled fork recovery, the association between the catalytic function of PTEN regulated by posttranslational modulation and cellular response to replication stress has not been studied explicitly. To understand molecular mechanism, we find that PTEN-null cells display unrestrained replication fork progression with accumulation of damaged DNA after treatment with aphidicolin which can be rescued by ectopic expression of full-length PTEN, as evident from DNA fiber assay. Moreover, the C-terminal phosphorylation (Ser 380, Thr 382/383) of PTEN is essential for its chromatin association and sensing replication stress that, in response, induce cell cycle arrest. Further, we observed that PTEN induces HP1α expression and H3K9me3 foci formation in a C-terminal phosphorylation-dependent manner. However, phosphatase dead PTEN cannot sense replication stress though it can be associated with chromatin. Together, our results suggest that DNA replication perturbation by aphidicolin enables chromatin association of PTEN through C-terminal phosphorylation, induces heterochromatin formation by stabilizing and up-regulating H3K9me3 foci and augments CHK1 activation. Thereby, PTEN prevents DNA replication fork elongation and simultaneously causes G1-S phase cell cycle arrest to limit cell proliferation in stress conditions. Thus PTEN act as stress sensing protein during replication arrest to maintain genomic stability.
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Affiliation(s)
- Sandip Misra
- PG Department of Microbiology, Bidhannagar College, EB-2 Sector-1, Saltlake, Kolkata, India
| | | | - Ginia Ghosh
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India
| | - Ananda Mukherjee
- Rajiv Gandhi Centre for Biotechnology,Thiruvananthapuram 695 014, Kerala, India
| | - Parimal Karmakar
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India.
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Feng X, Tang M, Dede M, Su D, Pei G, Jiang D, Wang C, Chen Z, Li M, Nie L, Xiong Y, Li S, Park JM, Zhang H, Huang M, Szymonowicz K, Zhao Z, Hart T, Chen J. Genome-wide CRISPR screens using isogenic cells reveal vulnerabilities conferred by loss of tumor suppressors. SCIENCE ADVANCES 2022; 8:eabm6638. [PMID: 35559673 PMCID: PMC9106303 DOI: 10.1126/sciadv.abm6638] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 10/02/2021] [Accepted: 03/30/2022] [Indexed: 05/05/2023]
Abstract
Exploiting cancer vulnerabilities is critical for the discovery of anticancer drugs. However, tumor suppressors cannot be directly targeted because of their loss of function. To uncover specific vulnerabilities for cells with deficiency in any given tumor suppressor(s), we performed genome-scale CRISPR loss-of-function screens using a panel of isogenic knockout cells we generated for 12 common tumor suppressors. Here, we provide a comprehensive and comparative dataset for genetic interactions between the whole-genome protein-coding genes and a panel of tumor suppressor genes, which allows us to uncover known and new high-confidence synthetic lethal interactions. Mining this dataset, we uncover essential paralog gene pairs, which could be a common mechanism for interpreting synthetic lethality. Moreover, we propose that some tumor suppressors could be targeted to suppress proliferation of cells with deficiency in other tumor suppressors. This dataset provides valuable information that can be further exploited for targeted cancer therapy.
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Affiliation(s)
- Xu Feng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mengfan Tang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Merve Dede
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Dan Su
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Guangsheng Pei
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Dadi Jiang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chao Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhen Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mi Li
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Litong Nie
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yun Xiong
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Siting Li
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jeong-Min Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huimin Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Min Huang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Klaudia Szymonowicz
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Traver Hart
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Junjie Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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13
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Wu S, Ge Y, Lin K, Liu Q, Zhou H, Hu Q, Zhao Y, He W, Ju Z. Telomerase RNA TERC and the PI3K-AKT pathway form a positive feedback loop to regulate cell proliferation independent of telomerase activity. Nucleic Acids Res 2022; 50:3764-3776. [PMID: 35323972 PMCID: PMC9023280 DOI: 10.1093/nar/gkac179] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/29/2021] [Revised: 02/11/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
The core catalytic unit of telomerase comprises telomerase reverse transcriptase (TERT) and telomerase RNA (TERC). Unlike TERT, which is predominantly expressed in cancer and stem cells, TERC is ubiquitously expressed in normal somatic cells without telomerase activity. However, the functions of TERC in these telomerase-negative cells remain elusive. Here, we reported positive feedback regulation between TERC and the PI3K-AKT pathway that controlled cell proliferation independent of telomerase activity in human fibroblasts. Mechanistically, we revealed that TERC activated the transcription of target genes from the PI3K-AKT pathway, such as PDPK1, by targeting their promoters. Overexpression of PDPK1 partially rescued the deficiency of AKT activation caused by TERC depletion. Furthermore, we found that FOXO1, a transcription factor negatively regulated by the PI3K-AKT pathway, bound to TERC promoter and suppressed its expression. Intriguingly, TERC-induced activation of the PI3K-AKT pathway also played a critical role in the proliferation of activated CD4+ T cells. Collectively, our findings identify a novel function of TERC that regulates the PI3K-AKT pathway via positive feedback to elevate cell proliferation independent of telomerase activity and provide a potential strategy to promote CD4+ T cells expansion that is responsible for enhancing adaptive immune reactions to defend against pathogens and tumor cells.
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Affiliation(s)
- Shu Wu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Yuanlong Ge
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China.,GCH Regenerative Medicine Group-Jinan University Joint Research and Development Center, Jinan University, Guangzhou 510632, China
| | - Kaixuan Lin
- Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Qianqian Liu
- First Affiliated Hospital, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Haoxian Zhou
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Qian Hu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Yong Zhao
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Weifeng He
- Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Army Military Medical University, Chongqing 400038, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
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14
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Chai C, Wu HH, Abuetabh Y, Sergi C, Leng R. Regulation of the tumor suppressor PTEN in triple-negative breast cancer. Cancer Lett 2022; 527:41-48. [PMID: 34902523 DOI: 10.1016/j.canlet.2021.12.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/20/2021] [Revised: 12/01/2021] [Accepted: 12/02/2021] [Indexed: 01/01/2023]
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BCa) in which estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) are not expressed. Although TNBC cases account for approximately 15% of all BCa cases, TNBC patients' prognosis is poor compared with that of other BCa subtypes. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays an important role in cell proliferation and migration by negatively regulating the PI3K/Akt pathway. PTEN is one of the most commonly inactivated tumor suppressors in BCa. PTEN inactivity is associated with larger tumor sizes, multiple lymph node metastases, and an aggressive triple-negative phenotype. This review primarily focuses on two key points: (1) PTEN and its function. (2) The regulation of tumor suppressor PTEN in TNBC. We provide a summary of genomic alterations of PTEN in BCa. We further discuss the transcriptional regulation of PTEN and how PTEN is regulated by posttranscription and posttranslational modification, as well as by protein interactions. Finally, we discuss the perspectives of the PTEN protein in TNBC.
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Affiliation(s)
- Chengsen Chai
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada; Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - H Helena Wu
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Yasser Abuetabh
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Consolato Sergi
- Division of Anatomical Pathology, Children's Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
| | - Roger Leng
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
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15
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Rasool R, Ullah I, Mubeen B, Alshehri S, Imam SS, Ghoneim MM, Alzarea SI, Al-Abbasi FA, Murtaza BN, Kazmi I, Nadeem MS. Theranostic Interpolation of Genomic Instability in Breast Cancer. Int J Mol Sci 2022; 23:ijms23031861. [PMID: 35163783 PMCID: PMC8836911 DOI: 10.3390/ijms23031861] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/18/2021] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 12/14/2022] Open
Abstract
Breast cancer is a diverse disease caused by mutations in multiple genes accompanying epigenetic aberrations of hazardous genes and protein pathways, which distress tumor-suppressor genes and the expression of oncogenes. Alteration in any of the several physiological mechanisms such as cell cycle checkpoints, DNA repair machinery, mitotic checkpoints, and telomere maintenance results in genomic instability. Theranostic has the potential to foretell and estimate therapy response, contributing a valuable opportunity to modify the ongoing treatments and has developed new treatment strategies in a personalized manner. “Omics” technologies play a key role while studying genomic instability in breast cancer, and broadly include various aspects of proteomics, genomics, metabolomics, and tumor grading. Certain computational techniques have been designed to facilitate the early diagnosis of cancer and predict disease-specific therapies, which can produce many effective results. Several diverse tools are used to investigate genomic instability and underlying mechanisms. The current review aimed to explore the genomic landscape, tumor heterogeneity, and possible mechanisms of genomic instability involved in initiating breast cancer. We also discuss the implications of computational biology regarding mutational and pathway analyses, identification of prognostic markers, and the development of strategies for precision medicine. We also review different technologies required for the investigation of genomic instability in breast cancer cells, including recent therapeutic and preventive advances in breast cancer.
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Affiliation(s)
- Rabia Rasool
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan; (R.R.); (I.U.); (B.M.)
| | - Inam Ullah
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan; (R.R.); (I.U.); (B.M.)
| | - Bismillah Mubeen
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan; (R.R.); (I.U.); (B.M.)
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (S.S.I.)
| | - Syed Sarim Imam
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (S.S.I.)
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia;
| | - Sami I. Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia;
| | - Fahad A. Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Bibi Nazia Murtaza
- Department of Zoology, Abbottabad University of Science and Technology (AUST), Abbottabad 22310, Pakistan;
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Correspondence: (I.K.); (M.S.N.)
| | - Muhammad Shahid Nadeem
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Correspondence: (I.K.); (M.S.N.)
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16
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Zhao Y, Ma T, Zhang Z, Chen X, Zhou C, Zhang L, Zou D. Resolvin D1 attenuates acid-induced DNA damage in esophageal epithelial cells and rat models of acid reflux. Eur J Pharmacol 2021; 912:174571. [PMID: 34656605 DOI: 10.1016/j.ejphar.2021.174571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/06/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 11/15/2022]
Abstract
The role of resolvin D1 (RvD1) in gastroesophageal reflux disease (GERD) remains largely unknown. Here, we investigated the potential role of RvD1 in acid-induced DNA damage in esophageal epithelial cells, patients with refractory GERD and a rat model of acid reflux. Weak acid exposure induced longer comet tails, reactive oxygen species (ROS) generation, oxidative DNA damage and DNA double-strand breaks (DSBs) in cells and RvD1 (0.1 μM) blocked all these effects. Mechanistic analyses showed that apart from ROS-reducing effects, RvD1 possessed a strong capacity to promote DNA damage repair, augmenting cell cycle checkpoint activity and DSB repair by modulating phosphatase and tensin homolog (PTEN) in cells. We also detected the surface expression of formyl peptide receptor 2 (FPR2), a receptor for RvD1, in the esophageal epithelial cells, and inhibition of FPR2 abrogated the protective effects of RvD1 on cells. Furthermore, a positive correlation between RvD1 and PTEN was observed predominantly in the esophageal epithelium from patients with refractory GERD (r = 0.67, P < 0.05). Additionally, RvD1 administration upregulated PTEN, suppressed DNA DSBs and alleviated microscopic damage in the rat model of gastric reflux. FPR2 gene silencing abolished the therapeutic effects of RvD1 on the rat model. Taken together, RvD1 binding to FPR2 protects the esophageal epithelium from acid reflux-induced DNA damage via a mechanism involving the inhibition of ROS production and facilitation of DSB repair. These findings support RvD1 as a promising approach that may be valuable for the treatment of GERD.
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Affiliation(s)
- Ye Zhao
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Teng Ma
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200030, China
| | - Zhihan Zhang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xi Chen
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chunhua Zhou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ling Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Duowu Zou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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17
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Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling. Cells 2021; 10:cells10123327. [PMID: 34943835 PMCID: PMC8699227 DOI: 10.3390/cells10123327] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/09/2021] [Revised: 11/12/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
The cell cycle is the series of events that take place in a cell, which drives it to divide and produce two new daughter cells. The typical cell cycle in eukaryotes is composed of the following phases: G1, S, G2, and M phase. Cell cycle progression is mediated by cyclin-dependent kinases (Cdks) and their regulatory cyclin subunits. However, the driving force of cell cycle progression is growth factor-initiated signaling pathways that control the activity of various Cdk–cyclin complexes. While the mechanism underlying the role of growth factor signaling in G1 phase of cell cycle progression has been largely revealed due to early extensive research, little is known regarding the function and mechanism of growth factor signaling in regulating other phases of the cell cycle, including S, G2, and M phase. In this review, we briefly discuss the process of cell cycle progression through various phases, and we focus on the role of signaling pathways activated by growth factors and their receptor (mostly receptor tyrosine kinases) in regulating cell cycle progression through various phases.
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18
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Misra S, Ghosh G, Chowdhury SG, Karmakar P. Non-canonical function of nuclear PTEN and its implication on tumorigenesis. DNA Repair (Amst) 2021; 107:103197. [PMID: 34359000 DOI: 10.1016/j.dnarep.2021.103197] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/11/2020] [Revised: 06/13/2021] [Accepted: 07/26/2021] [Indexed: 01/13/2023]
Abstract
Suppression of genomic instability is the key to prevent tumor development. PTEN is a unique tumor suppressor protein having both lipid and protein phosphatase activities. Interestingly though it is a cytoplasmic protein, but a significant pool of PTEN can also be localized in nucleus. The function of cytoplasmic PTEN is well defined and extensively studied in various literatures focusing mainly on the negative regulation of oncogenic PI-3Kinase-AKT pathway but functional regulation of nuclear PTEN is less defined and therefore it is a fascinating subject of research in cancer biology. Post-translation modulation of PTEN such as phosphorylation, sumorylation, acetylation and methylation also regulates its cellular localization, protein-protein association and catalytic function. Loss or mutation in PTEN is associated with the development of tumors in various tissues from the brain to prostate. Here we have summarized the role of nuclear PTEN and its epigenetic modulation in various DNA metabolic pathways, for example, DNA damage response, DNA repair, DNA replication, DNA segregation etc. Further, pathways involved in nuclear PTEN degradation are also discussed. Additionally, we also emphasize probable potential targets associated with PTEN pathway for chemotherapeutic purpose.
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Affiliation(s)
- Sandip Misra
- PG Department of Microbiology, Bidhannagar College, EB-2 Sector-1, Saltlake, Kolkata, India
| | - Ginia Ghosh
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India
| | | | - Parimal Karmakar
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India.
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19
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Myint ZW, Allison DB, Ellis CS. A Case Report of Metastatic Castration-Resistant Prostate Cancer Harboring a PTEN Loss. Front Oncol 2021; 11:731002. [PMID: 34631559 PMCID: PMC8495426 DOI: 10.3389/fonc.2021.731002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/25/2021] [Accepted: 08/27/2021] [Indexed: 11/22/2022] Open
Abstract
The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has dramatically improved over the last decade; however, patients with visceral metastases are still faced with poor outcomes. Phosphatase and tensin homolog (PTEN) loss is observed in 40%–60% of mCRPC patients and is also associated with a poor prognosis. Several PI3K/AKT/mTOR pathway inhibitors have been studied, with disappointing anti-tumor activity. Here, we present a case of a patient with heavily treated mCRPC who had a modest tumor response to concurrent carboplatin, abiraterone acetate/prednisone, and liver-directed radiation therapy. We discuss the potential rationale supporting the use of this combination therapy and its safety in mCRPC. While the underlying basic mechanism of our patient’s anti-tumor response remains uncertain, we suggest that further prospective studies are warranted to evaluate whether this combination therapy is effective in this population of patients with pre-treated mCRPC and PTEN loss.
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Affiliation(s)
- Zin W Myint
- Department of Internal Medicine, Division of Medical Oncology, University of Kentucky, Lexington, KY, United States.,Markey Cancer Center, University of Kentucky, Lexington, KY, United States
| | - Derek B Allison
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States.,Department of Urology, University of Kentucky, Lexington, KY, United States.,Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, United States
| | - Carleton S Ellis
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States.,Department of Pharmacy, University of Kentucky, Lexington KY, United States
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20
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Alemi F, Raei Sadigh A, Malakoti F, Elhaei Y, Ghaffari SH, Maleki M, Asemi Z, Yousefi B, Targhazeh N, Majidinia M. Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk. J Cell Physiol 2021; 237:313-328. [PMID: 34515349 DOI: 10.1002/jcp.30573] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/28/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 12/14/2022]
Abstract
The cellular genome is frequently subjected to abundant endogenous and exogenous factors that induce DNA damage. Most of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family members are activated in response to DNA damage and are the most important DNA damage response (DDR) proteins. The DDR system protects the cells against the wrecking effects of these genotoxicants and repairs the DNA damage caused by them. If the DNA damage is severe, such as when DNA is the goal of chemo-radiotherapy, the DDR drives cells toward cell cycle arrest and apoptosis. Some intracellular pathways, such as PI3K/Akt, which is overactivated in most cancers, could stimulate the DDR process and failure of chemo-radiotherapy with the increasing repair of damaged DNA. This signaling pathway induces DNA repair through the regulation of proteins that are involved in DDR like BRCA1, HMGB1, and P53. In this review, we will focus on the crosstalk of the PI3K/Akt and PIKKs involved in DDR and then discuss current achievements in the sensitization of cancer cells to chemo-radiotherapy by PI3K/Akt inhibitors.
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Affiliation(s)
- Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aydin Raei Sadigh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Malakoti
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yusuf Elhaei
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Hamed Ghaffari
- Department of Orthopedics, Shohada Medical Research & Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masomeh Maleki
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Bahman Yousefi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
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21
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Choudhuri S, Kaur T, Jain S, Sharma C, Asthana S. A review on genotoxicity in connection to infertility and cancer. Chem Biol Interact 2021; 345:109531. [PMID: 34058178 DOI: 10.1016/j.cbi.2021.109531] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/22/2020] [Revised: 04/22/2021] [Accepted: 05/17/2021] [Indexed: 10/21/2022]
Abstract
Genotoxicity has been identified as the main cause of infertility and a variety of cancers. The mechanisms affect the structure, quality of the information or the segregation of DNA and are not inherently correlated with mutagenicity. The concept of genotoxicity, the chemical classes that cause genetic damage and the associated mechanisms of action are discussed here. Hazardous effects of pharmaceuticals, cosmetics, agrochemicals, industrial compounds, food additives, natural toxins and nanomaterials are, in large part, identified by genotoxicity and mutagenicity tests. These are critical and early steps in industrial and regulatory health assessment. Though several in vitro experiments are commonly used and approval by regulatory agencies for commercial licensing of drugs, their accuracy in human predictions for genotoxic and mutagenic effects is frequently questioned. Treatment of real and functional genetic toxicity problems depends in detail on the knowledge of mechanisms of DNA damage in the molecular, subcellular, cellular and tissue or organ system levels. Current strategies for risk assessment of human health need revisions to achieve robust and reliable results for optimizing their effectiveness. Additionally, computerized methods, neo-biomarkers leveraging '-omics' approaches, all of which can provide a convincing genotoxicity evaluation to reduce infertility and cancer risk.
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Affiliation(s)
- Sharmistha Choudhuri
- Department of Biochemistry, R. G. Kar Medical College and Hospital, Kolkata, West Bengal, India
| | - Taruneet Kaur
- Animal Biochemistry Division, National Dairy Research Institute, Karnal, Haryana, India
| | - Sapna Jain
- Multidisciplinary Clinical Translational Research, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Chandresh Sharma
- Multidisciplinary Clinical Translational Research, Translational Health Science and Technology Institute, Faridabad, Haryana, India.
| | - Shailendra Asthana
- Non-Communicable Disease, Translational Health Science and Technology Institute, Faridabad, Haryana, India.
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22
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Cai J, Wang N, Lin G, Zhang H, Xie W, Zhang Y, Xu N. MBNL2 Regulates DNA Damage Response via Stabilizing p21. Int J Mol Sci 2021; 22:ijms22020783. [PMID: 33466733 PMCID: PMC7829980 DOI: 10.3390/ijms22020783] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/20/2020] [Revised: 12/31/2020] [Accepted: 01/12/2021] [Indexed: 12/14/2022] Open
Abstract
RNA-binding proteins are frequently dysregulated in human cancer and able to modulate tumor cell proliferation as well as tumor metastasis through post-transcriptional regulation on target genes. Abnormal DNA damage response and repair mechanism are closely related to genome instability and cell transformation. Here, we explore the function of the RNA-binding protein muscleblind-like splicing regulator 2 (MBNL2) on tumor cell proliferation and DNA damage response. Transcriptome and gene expression analysis show that the PI3K/AKT pathway is enriched in MBNL2-depleted cells, and the expression of cyclin-dependent kinase inhibitor 1A (p21CDKN1A) is significantly affected after MBNL2 depletion. MBNL2 modulates the mRNA and protein levels of p21, which is independent of its canonical transcription factor p53. Moreover, depletion of MBNL2 increases the phosphorylation levels of checkpoint kinase 1 (Chk1) serine 345 (S345) and DNA damage response, and the effect of MBNL2 on DNA damage response is p21-dependent. MBNL2 would further alter tumor cell fate after DNA damage, MBNL2 knockdown inhibiting DNA damage repair and DNA damage-induced senescence, but promoting DNA damage-induced apoptosis.
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Affiliation(s)
- Jin Cai
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.C.); (N.W.); (G.L.); (H.Z.); (W.X.); (Y.Z.)
- Open FIESTA Center, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Ningchao Wang
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.C.); (N.W.); (G.L.); (H.Z.); (W.X.); (Y.Z.)
- Open FIESTA Center, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Guanglan Lin
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.C.); (N.W.); (G.L.); (H.Z.); (W.X.); (Y.Z.)
- Open FIESTA Center, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Haowei Zhang
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.C.); (N.W.); (G.L.); (H.Z.); (W.X.); (Y.Z.)
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Weidong Xie
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.C.); (N.W.); (G.L.); (H.Z.); (W.X.); (Y.Z.)
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yaou Zhang
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.C.); (N.W.); (G.L.); (H.Z.); (W.X.); (Y.Z.)
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Naihan Xu
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.C.); (N.W.); (G.L.); (H.Z.); (W.X.); (Y.Z.)
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Correspondence:
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23
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Ferreira RG, Narvaez LEM, Espíndola KMM, Rosario ACRS, Lima WGN, Monteiro MC. Can Nimesulide Nanoparticles Be a Therapeutic Strategy for the Inhibition of the KRAS/PTEN Signaling Pathway in Pancreatic Cancer? Front Oncol 2021; 11:594917. [PMID: 34354940 PMCID: PMC8329661 DOI: 10.3389/fonc.2021.594917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/14/2020] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is an aggressive, devastating disease due to its invasiveness, rapid progression, and resistance to surgical, pharmacological, chemotherapy, and radiotherapy treatments. The disease develops from PanINs lesions that progress through different stages. KRAS mutations are frequently observed in these lesions, accompanied by inactivation of PTEN, hyperactivation of the PI3K/AKT pathway, and chronic inflammation with overexpression of COX-2. Nimesulide is a selective COX-2 inhibitor that has shown anticancer effects in neoplastic pancreatic cells. This drug works by increasing the levels of PTEN expression and inhibiting proliferation and apoptosis. However, there is a need to improve nimesulide through its encapsulation by solid lipid nanoparticles to overcome problems related to the hepatotoxicity and bioavailability of the drug.
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Affiliation(s)
- Roseane Guimarães Ferreira
- Neuroscience and Cell Biology Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Biological Sciences Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Luis Eduardo Mosquera Narvaez
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Kaio Murilo Monteiro Espíndola
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Amanda Caroline R. S. Rosario
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Wenddy Graziela N. Lima
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
| | - Marta Chagas Monteiro
- Neuroscience and Cell Biology Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Biological Sciences Institute, Federal University of Pará/UFPA, Belém, Brazil
- Pharmaceutical Science Post-Graduation Program, Laboratory of In Vitro Tests, Immunology and Microbiology-LABEIM, Health Science Institute, Federal University of Pará/UFPA, Belém, Brazil
- *Correspondence: Marta Chagas Monteiro,
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ATM Kinase Inhibition Preferentially Sensitises PTEN-Deficient Prostate Tumour Cells to Ionising Radiation. Cancers (Basel) 2020; 13:cancers13010079. [PMID: 33396656 PMCID: PMC7794981 DOI: 10.3390/cancers13010079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/16/2020] [Revised: 12/18/2020] [Accepted: 12/23/2020] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Prostate cancer is the most frequently diagnosed cancer in men. Despite the importance of radical radiotherapy for the management of this disease, recurrence remains a challenge. PTEN is a tumour suppressor that is frequently inactivated in advanced prostate cancer and has been associated with relapse following radiotherapy. The present study shows that the role of PTEN in response to ionizing radiation is complex. Furthermore, it demonstrates that in the absence of PTEN, an increased response to combined treatment using radiotherapy and the ATM inhibitor KU-60019 can be observed. Our findings provide a strong rationale for evaluating loss of PTEN in prostate cancer as a therapeutic target for ATM inhibitor in combination with radiotherapy in the clinical setting. Abstract Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8–18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.
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25
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Fiuji H, Nassiri M. Gene expression profiling of chromosome 10 in PTEN-knockout (−/−) human neural and mesenchymal stem cells: A system biology study. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/25/2022]
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26
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Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C. Cells 2020; 9:cells9112408. [PMID: 33153119 PMCID: PMC7693681 DOI: 10.3390/cells9112408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/05/2020] [Revised: 10/22/2020] [Accepted: 10/28/2020] [Indexed: 12/16/2022] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is a rare subtype of gynecological cancer for which well-characterized and authenticated model systems are scarce. We provide an extensive characterization of ‘105C’, a cell line generated from an adenocarcinoma of the clear cell histotype using targeted next-generation sequencing, cytogenetic microarrays, along with analyses of AKT/mTOR signaling. We report that that the 105C cell line is a bona fide OCCC cell line, carrying PIK3CA, PTEN, and ARID1A gene mutations, consistent with OCCC, yet maintain a stable genome as reflected by low copy number variation. Unlike KOC-7c, TOV-21G, and RMG-V OCCC lines also mutated for the above genes, the 105C cells do not carry mutations in mismatch repair genes. Importantly, we show that 105C cells exhibit greater resistance to mTOR inhibition and carboplatin treatment compared to 9 other OCCC cell lines in 3D spheroid cultures. This resistance may be attributed to 105C cells remaining dormant in suspension culture which surprisingly, contrasts with several other OCCC lines which continue to proliferate in long-term suspension culture. 105C cells survive xenotransplantation but do not proliferate and metastasize. Collectively, we show that the 105C OCCC cell line exhibits unique properties useful for the pre-clinical investigation of OCCC pathobiology.
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27
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Turnham DJ, Bullock N, Dass MS, Staffurth JN, Pearson HB. The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer. Cells 2020; 9:E2342. [PMID: 33105713 PMCID: PMC7690430 DOI: 10.3390/cells9112342] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/08/2020] [Revised: 10/17/2020] [Accepted: 10/20/2020] [Indexed: 12/17/2022] Open
Abstract
Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K-AKT-mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K-AKT-mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.
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Affiliation(s)
- Daniel J. Turnham
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (D.J.T.); (N.B.); (M.S.D.)
| | - Nicholas Bullock
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (D.J.T.); (N.B.); (M.S.D.)
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK;
| | - Manisha S. Dass
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (D.J.T.); (N.B.); (M.S.D.)
| | - John N. Staffurth
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK;
| | - Helen B. Pearson
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (D.J.T.); (N.B.); (M.S.D.)
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28
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Sinha D, Nag P, Nanayakkara D, Duijf PHG, Burgess A, Raninga P, Smits VAJ, Bain AL, Subramanian G, Wall M, Finnie JW, Kalimutho M, Khanna KK. Cep55 overexpression promotes genomic instability and tumorigenesis in mice. Commun Biol 2020; 3:593. [PMID: 33087841 PMCID: PMC7578791 DOI: 10.1038/s42003-020-01304-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/18/2019] [Accepted: 09/17/2020] [Indexed: 12/16/2022] Open
Abstract
High expression of centrosomal protein CEP55 has been correlated with clinico-pathological parameters across multiple human cancers. Despite significant in vitro studies and association of aberrantly overexpressed CEP55 with worse prognosis, its causal role in vivo tumorigenesis remains elusive. Here, using a ubiquitously overexpressing transgenic mouse model, we show that Cep55 overexpression causes spontaneous tumorigenesis and accelerates Trp53+/− induced tumours in vivo. At the cellular level, using mouse embryonic fibroblasts (MEFs), we demonstrate that Cep55 overexpression induces proliferation advantage by modulating multiple cellular signalling networks including the hyperactivation of the Pi3k/Akt pathway. Notably, Cep55 overexpressing MEFs have a compromised Chk1-dependent S-phase checkpoint, causing increased replication speed and DNA damage, resulting in a prolonged aberrant mitotic division. Importantly, this phenotype was rescued by pharmacological inhibition of Pi3k/Akt or expression of mutant Chk1 (S280A) protein, which is insensitive to regulation by active Akt, in Cep55 overexpressing MEFs. Moreover, we report that Cep55 overexpression causes stabilized microtubules. Collectively, our data demonstrates causative effects of deregulated Cep55 on genome stability and tumorigenesis which have potential implications for tumour initiation and therapy development. Sinha et al. demonstrate that overexpression of centrosomal protein Cep55 in mice is sufficient to cause a wide-spectrum of cancer via multiple mechanisms including hyperactivation of the Pi3k/Akt pathway, stabilized microtubules and a defective replication checkpoint response. These findings are relevant to human cancers as high CEP55 expression is associated with worse prognosis across multiple cancer types.
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Affiliation(s)
- Debottam Sinha
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia.,School of Environment and Sciences, Griffith University, Nathan, 4111, QLD, Australia
| | - Purba Nag
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia.,School of Environment and Sciences, Griffith University, Nathan, 4111, QLD, Australia.,Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland and Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, 4029, QLD, Australia
| | - Devathri Nanayakkara
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia
| | - Pascal H G Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, 4102, QLD, Australia.,Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Andrew Burgess
- ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia
| | - Prahlad Raninga
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia
| | - Veronique A J Smits
- Unidad de Investigación, Hospital Universitario de Canarias, Tenerife, Spain.,Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Tenerife, Spain.,Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
| | - Amanda L Bain
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia
| | - Goutham Subramanian
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia
| | - Meaghan Wall
- Victorian Cancer Cytogenetics Service, St. Vincent's Hospital, Fitzroy, Melbourne, Australia
| | - John W Finnie
- Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide and SA Pathology, Adelaide, Australia
| | - Murugan Kalimutho
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia.
| | - Kum Kum Khanna
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia.
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29
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Arumugam T, Ghazi T, Chuturgoon A. Fumonisin B 1 Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells. Toxins (Basel) 2020; 12:toxins12100625. [PMID: 33007920 PMCID: PMC7601513 DOI: 10.3390/toxins12100625] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/23/2020] [Revised: 08/19/2020] [Accepted: 08/27/2020] [Indexed: 12/13/2022] Open
Abstract
Fumonisin B1 (FB1), a Fusarium-produced mycotoxin, is found in various foods and feeds. It is a well-known liver carcinogen in experimental animals; however, its role in genotoxicity is controversial. The current study investigated FB1-triggered changes in the epigenetic regulation of PTEN and determined its effect on DNA damage checkpoint regulation in human liver hepatoma G2 (HepG2) cells. Following treatment with FB1 (IC50: 200 µM; 24 h), the expression of miR-30c, KDM5B, PTEN, H3K4me3, PI3K, AKT, p-ser473-AKT, CHK1, and p-ser280-CHK1 was measured using qPCR and/or Western blot. H3K4me3 enrichment at the PTEN promoter region was assayed via a ChIP assay and DNA damage was determined using an ELISA. FB1 induced oxidative DNA damage. Total KDM5B expression was reduced, which subsequently increased the total H3K4me3 and the enrichment of H3K4me3 at PTEN promoters. Increased H3K4me3 induced an increase in PTEN transcript levels. However, miR-30c inhibited PTEN translation. Thus, PI3K/AKT signaling was activated, inhibiting CHK1 activity via phosphorylation of its serine 280 residue preventing the repair of damaged DNA. In conclusion, FB1 epigenetically modulates the PTEN/PI3K/AKT signaling cascade, preventing DNA damage checkpoint regulation, and induces significant DNA damage.
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30
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Neizer-Ashun F, Bhattacharya R. Reality CHEK: Understanding the biology and clinical potential of CHK1. Cancer Lett 2020; 497:202-211. [PMID: 32991949 DOI: 10.1016/j.canlet.2020.09.016] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/02/2020] [Revised: 08/26/2020] [Accepted: 09/20/2020] [Indexed: 12/13/2022]
Abstract
The DNA damage response enables cells to cope with various stresses that threaten genomic integrity. A critical component of this response is the serine/threonine kinase CHK1 which is encoded by the CHEK1 gene. Originally identified as a regulator of the G2/M checkpoint, CHK1 has since been shown to play important roles in DNA replication, mitotic progression, DNA repair, and overall cell cycle regulation. However, the potential of CHK1 as a cancer therapy has not been realized clinically. Herein we expound our current understanding of the principal roles of CHK1 and highlight different avenues for CHK1 targeting in cancer therapy.
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Affiliation(s)
- Fiifi Neizer-Ashun
- Department of Cell Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, 73104, United States
| | - Resham Bhattacharya
- Department of Cell Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, 73104, United States; Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, United States; Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, 73104, United States.
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31
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Akt+ IKKα/β+ Rab5+ Signalosome Mediate the Endosomal Recruitment of Sec61 and Contribute to Cross-Presentation in Bone Marrow Precursor Cells. Vaccines (Basel) 2020; 8:vaccines8030539. [PMID: 32957586 PMCID: PMC7563657 DOI: 10.3390/vaccines8030539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/08/2020] [Revised: 09/15/2020] [Accepted: 09/15/2020] [Indexed: 12/25/2022] Open
Abstract
Cross-presentation in dendritic cells (DC) requires the endosomal relocations of internalized antigens and the endoplasmic reticulum protein Sec61. Despite the fact that endotoxin-containing pathogen and endotoxin-free antigen have different effects on protein kinase B (Akt) and I-kappa B Kinase α/β (IKKα/β) activation, the exact roles of Akt phosphorylation, IKKα or IKKβ activation in endotoxin-containing pathogen-derived cross-presentation are poorly understood. In this study, endotoxin-free ovalbumin supplemented with endotoxin was used as a model pathogen. We investigated the effects of endotoxin-containing pathogen and endotoxin-free antigen on Akt phosphorylation, IKKα/β activation, and explored the mechanisms that the endotoxin-containing pathogen orchestrating the endosomal recruitment of Sec61 of the cross-presentation in bone marrow precursor cells (BMPC). We demonstrated that endotoxin-containing pathogen and endotoxin-free antigen efficiently induced the phosphorylation of Akt-IKKα/β and Akt-IKKα, respectively. Endotoxin-containing pathogen derived Akt+ IKKα/β+ Rab5+ signalosome, together with augmented the recruitment of Sec61 toward endosome, lead to the increased cross-presentation in BMPC. Importantly, the endosomal recruitment of Sec61 was partly mediated by the formation of Akt+ IKKα/β+ signalosome. Thus, these data suggest that Akt+ IKKα/β+ Rab5+ signalosome contribute to endotoxin-containing pathogen-induced the endosomal recruitment of Sec61 and the superior efficacy of cross-presentation in BMPC.
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32
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Fan X, Kraynak J, Knisely JPS, Formenti SC, Shen WH. PTEN as a Guardian of the Genome: Pathways and Targets. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a036194. [PMID: 31932469 DOI: 10.1101/cshperspect.a036194] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
Faithful transmission of genetic information is only possible with the structural and functional integrity of the genome. PTEN has been recognized as a guardian of the genome since the identification of its noncanonical localization and function in the nucleus. Yet, the role of PTEN in guarding the genome relies on integration of diverse mechanisms elicited by its canonical activity in antagonizing PI3K as well as emerging noncanonical functions. In the nucleus, PTEN maintains the structural integrity of chromosomes and the architecture of heterochromatin by physically interacting with chromosomal and nucleosomal components. PTEN also controls the functional integrity of key genetic transmission machineries by promoting proper assembly of the replisome and mitotic spindles. Deregulation of PTEN signaling impairs genome integrity, leading to spontaneous replication/mitotic stress and subsequent stress tolerance. Identification of novel targets of PTEN signaling and illumination of the interplay of diverse PTEN pathways in genome maintenance will help us better understand mechanisms underlying tumor evolution and therapeutic resistance.
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Affiliation(s)
- Xinyi Fan
- Department of Radiation Oncology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA
| | - Jeffrey Kraynak
- Department of Radiation Oncology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA
| | - Jonathan P S Knisely
- Department of Radiation Oncology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA
| | - Silvia C Formenti
- Department of Radiation Oncology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA
| | - Wen H Shen
- Department of Radiation Oncology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA
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33
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Chen C, Zhu S, Zhang X, Zhou T, Gu J, Xu Y, Wan Q, Qi X, Chai Y, Liu X, Chen L, Yan J, Hua Y, Lin F. Targeting the Synthetic Vulnerability of PTEN-Deficient Glioblastoma Cells with MCL1 Inhibitors. Mol Cancer Ther 2020; 19:2001-2011. [PMID: 32737157 DOI: 10.1158/1535-7163.mct-20-0099] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/08/2020] [Revised: 05/17/2020] [Accepted: 07/08/2020] [Indexed: 11/16/2022]
Abstract
PTEN deletion or mutation occurs in 30% to 60% of patients with glioblastoma (GBM) and is associated with poor prognosis. Efficacious therapy for this subgroup of patients is currently lacking. To identify potential target(s) to selectively suppress PTEN-deficient GBM growth, we performed a three-step synthetic lethal screen on LN18 PTEN wild-type (WT) and knockout (KO) isogeneic GBM cell lines using a library containing 606 target-selective inhibitors. A MCL1 inhibitor UMI-77 identified in the screen exhibited excellent suppression on the proliferation, colony formation, 3D spheroid, and neurosphere formation of PTEN-deficient GBM cells. Mechanistically, loss of PTEN in GBM cells led to upregulation of MCL1 in posttranslational level via inhibition of GSK3β, and consequently confer cells resistance to apoptosis. Pharmacologic inhibition or knockdown of MCL1 blocked this PI3K-GSK3β-MCL1 axis and caused reduction of several antiapoptotic proteins, finally induced massive caspase-3 cleavage and apoptosis. In both subcutaneous and orthotopic GBM models, knockdown of MCL1 significantly impaired the in vivo growth of PTEN-deficient xenografts. Moreover, the combination of UMI-77 and temozolomide synergistically killed PTEN-deficient GBM cells. Collectively, our work identified MCL1 as a promising target for PTEN-deficient GBM. For future clinical investigations, priority should be given to the development of a selective MCL1 inhibitor with efficient brain delivery and minimal in vivo toxicity.
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Affiliation(s)
- Chao Chen
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Sichao Zhu
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Xia Zhang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Tingting Zhou
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Jing Gu
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Yurong Xu
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Quan Wan
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Xiao Qi
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Yezi Chai
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Xiaorong Liu
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Lukui Chen
- Department of Neurosurgery, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Jie Yan
- Department of Forensic Science, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yunfen Hua
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China
| | - Fan Lin
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. .,Institute for Brain Tumors & Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University; The Affiliated Cancer Hospital of Nanjing Medical University; Key Laboratory of Human Functional Genomics of Jiangsu Province; Nanjing, China
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Huang J, Li JJ. Multiple Dynamics in Tumor Microenvironment Under Radiotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1263:175-202. [PMID: 32588328 DOI: 10.1007/978-3-030-44518-8_10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023]
Abstract
The tumor microenvironment (TME) is an evolutionally low-level and embryonically featured tissue comprising heterogenic populations of malignant and stromal cells as well as noncellular components. Under radiotherapy (RT), the major modality for the treatment of malignant diseases [1], TME shows an adaptive response in multiple aspects that affect the efficacy of RT. With the potential clinical benefits, interests in RT combined with immunotherapy (IT) are intensified with a large scale of clinical trials underway for an array of cancer types. A better understanding of the multiple molecular aspects, especially the cross talks of RT-mediated energy reprogramming and immunoregulation in the irradiated TME (ITME), will be necessary for further enhancing the benefit of RT-IT modality. Coming studies should further reveal more mechanistic insights of radiation-induced instant or permanent consequence in tumor and stromal cells. Results from these studies will help to identify critical molecular pathways including cancer stem cell repopulation, metabolic rewiring, and specific communication between radioresistant cancer cells and the infiltrated immune active lymphocytes. In this chapter, we will focus on the following aspects: radiation-repopulated cancer stem cells (CSCs), hypoxia and re-oxygenation, reprogramming metabolism, and radiation-induced immune regulation, in which we summarize the current literature to illustrate an integrated image of the ITME. We hope that the contents in this chapter will be informative for physicians and translational researchers in cancer radiotherapy or immunotherapy.
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Affiliation(s)
- Jie Huang
- Department of Radiation Oncology, University of California Davis, Sacramento, CA, USA
| | - Jian Jian Li
- Department of Radiation Oncology, University of California Davis, Sacramento, CA, USA. .,NCI-Designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
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35
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Brunner A, Suryo Rahmanto A, Johansson H, Franco M, Viiliäinen J, Gazi M, Frings O, Fredlund E, Spruck C, Lehtiö J, Rantala JK, Larsson LG, Sangfelt O. PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer. eLife 2020; 9:57894. [PMID: 32628111 PMCID: PMC7338058 DOI: 10.7554/elife.57894] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/16/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Inhibition of WEE1 kinase by AZD1775 has shown promising results in clinical cancer trials, but markers predicting AZD1775 response are lacking. Here we analysed AZD1775 response in a panel of human breast cancer (BC) cell lines by global proteome/transcriptome profiling and identified two groups of basal-like BC (BLBCs): ‘PTEN low’ BLBCs were highly sensitive to AZD1775 and failed to recover following removal of AZD1775, while ‘PTEN high’ BLBCs recovered. AZD1775 induced phosphorylation of DNA-PK, protecting cells from replication-associated DNA damage and promoting cellular recovery. Deletion of DNA-PK or PTEN, or inhibition of DNA-PK sensitized recovering BLBCs to AZD1775 by abrogating replication arrest, allowing replication despite DNA damage. This was linked to reduced CHK1 activation, increased cyclin E levels and apoptosis. In conclusion, we identified PTEN and DNA-PK as essential regulators of replication checkpoint arrest in response to AZD1775 and defined PTEN as a promising biomarker for efficient WEE1 cancer therapy.
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Affiliation(s)
- Andrä Brunner
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | | | - Henrik Johansson
- Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Marcela Franco
- Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden
| | - Johanna Viiliäinen
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Mohiuddin Gazi
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Oliver Frings
- Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Erik Fredlund
- Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Charles Spruck
- Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
| | - Janne Lehtiö
- Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Juha K Rantala
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Lars-Gunnar Larsson
- Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden
| | - Olle Sangfelt
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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36
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Fusco N, Sajjadi E, Venetis K, Gaudioso G, Lopez G, Corti C, Rocco EG, Criscitiello C, Malapelle U, Invernizzi M. PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine? Genes (Basel) 2020; 11:E719. [PMID: 32605290 PMCID: PMC7397204 DOI: 10.3390/genes11070719] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/05/2020] [Revised: 06/27/2020] [Accepted: 06/27/2020] [Indexed: 12/15/2022] Open
Abstract
Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, PTEN is deeply involved in cell growth, proliferation, and survival. This gene is also implicated in the modulation of the DNA damage response and in tumor immune microenvironment modeling. Despite the actionability of PTEN alterations, their role as biomarkers remains controversial in clinical practice. To date, there is still a substantial lack of validated guidelines and/or recommendations for PTEN testing. Here, we provide an update on the current state of knowledge on biologic and genetic alterations of PTEN across the most frequent solid tumors, as well as on their actual and/or possible clinical applications. We focus on possible tailored schemes for cancer patients' clinical management, including risk assessment, diagnosis, prognostication, and treatment.
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Affiliation(s)
- Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (K.V.); (E.G.R.)
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
| | - Elham Sajjadi
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
| | - Konstantinos Venetis
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (K.V.); (E.G.R.)
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
- Doctoral Program in Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Gabriella Gaudioso
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20131 Milan, Italy; (G.G.); (G.L.); (C.C.)
| | - Gianluca Lopez
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20131 Milan, Italy; (G.G.); (G.L.); (C.C.)
| | - Chiara Corti
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20131 Milan, Italy; (G.G.); (G.L.); (C.C.)
| | - Elena Guerini Rocco
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (K.V.); (E.G.R.)
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
| | - Carmen Criscitiello
- New Drugs and Early Drug Development for Innovative Therapies Division, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy;
| | - Umberto Malapelle
- Department of Public Health, University Federico II, 80138 Naples, Italy;
| | - Marco Invernizzi
- Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy;
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37
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Li J, Jiang D, Zhang Q, Peng S, Liao G, Yang X, Tang J, Xiong H, Pang J. MiR-301a Promotes Cell Proliferation by Repressing PTEN in Renal Cell Carcinoma. Cancer Manag Res 2020; 12:4309-4320. [PMID: 32606927 PMCID: PMC7294045 DOI: 10.2147/cmar.s253533] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/11/2020] [Accepted: 05/30/2020] [Indexed: 12/15/2022] Open
Abstract
Objective Renal cell carcinoma (RCC) displays an increasing incidence and mortality rate worldwide in recent years. More and more evidence demonstrated microRNAs function as positive or negative regulatory factors in many cancers, while the role of miR-301a in RCC is still unclear. Material and Methods The expression and clinical significance of miR-301a were assessed via bioinformatic software on open microarray datasets of the Cancer Genome Atlas (TCGA) and then confirmed by quantitative real-time PCR (qRT-PCR) in RCC cell lines. Loss of function assays were performed in RCC cell lines both in vitro and in vivo. Cell Counting Kit-8 (CCK-8), flow cytometry, luciferase reporter assays, Western blotting, and immunohistochemistry were employed to explore the mechanisms of the effect of miR-301a on RCC. Results By analyzing RCC clinical specimens and cell lines, we found a uniform increased miR-301a in expression in comparison with normal renal tissue or normal human proximal tubule epithelial cell line (HK-2). In addition, miR-301a upregulation correlated advanced stage and poor prognosis of clear cell RCC (ccRCC). Anti-miR-301a could inhibit growth and cell cycle G1/S transition in RCC cell lines. Moreover, we found that PTEN was identified as a direct target of miR-301a that might partially interrupt miR-301a-induced G1/S transition. Importantly, nude-mouse models revealed that knockdown of miR-301a delayed tumor growth. Conclusion These results indicate that miR-301a functions as a tumor-promoting miRNA through regulating PTEN expression, representing a novel therapeutic target for RCC.
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Affiliation(s)
- Jun Li
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Donggen Jiang
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Qian Zhang
- Department of Rehabilitation Medicine, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Shubin Peng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Guolong Liao
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Xiangwei Yang
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Jiani Tang
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Haiyun Xiong
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Jun Pang
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
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38
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Mikhaleva LM, Davydov AI, Patsap OI, Mikhaylenko EV, Nikolenko VN, Neganova ME, Klochkov SG, Somasundaram SG, Kirkland CE, Aliev G. Malignant Transformation and Associated Biomarkers of Ovarian Endometriosis: A Narrative Review. Adv Ther 2020; 37:2580-2603. [PMID: 32385745 PMCID: PMC7467438 DOI: 10.1007/s12325-020-01363-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/13/2020] [Indexed: 02/07/2023]
Abstract
This review focuses on pathogenesis of endometriosis, its possible biomarkers and role in endometriosis-associated ovarian cancer. We analyzed various databases to obtain new insights, theories, and biomarkers associated with endometriosis. There are several theories of endometriosis development and biomarker changes including atypical forms. A number of studies have attempted to establish specific, reliable biomarkers to help diagnose endometriosis and endometriosis-associated diseases on the basis of different pathogenetic pathways. Nevertheless, despite intensive research extending even to the molecular level, the origin, natural history, malignant transformation, and laboratory management of endometriosis and related diseases are not yet clearly defined. Therefore, early laboratory diagnoses of endometriosis, its atypical form, and endometriosis-associated ovarian tumors are important problems that require further study in the context of advanced therapeutic strategies to provide maximal health benefits to patients.
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Affiliation(s)
- Liudmila M Mikhaleva
- Department of Clinical Pathology, Federal State Budgetary Institution "Research Institute of Human Morphology", 3, Tsyurupy Str, Moscow, 117418, Russian Federation
| | - Aleksandr I Davydov
- Department of Obstetrics, Gynecology and Perinatology, Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2, Trubetskaya Str., Moscow, 119991, Russian Federation
- Department of Pathology, City Clinical Hospital After Named S.S. Udina, 4, Bld., 3, Kolomensky Passage, Moscow, 115446, Russian Federation
| | - Olga I Patsap
- Department of Pathology, City Clinical Hospital After Named S.S. Udina, 4, Bld., 3, Kolomensky Passage, Moscow, 115446, Russian Federation
| | - Elizaveta V Mikhaylenko
- I. M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia
| | - Vladimir N Nikolenko
- I. M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia
- Department of Normal and Topographic Anatomy, M.V. Lomonosov Moscow State University, Leninskie Gory, 1, Moscow, 119991, Russia
| | - Margarita E Neganova
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severny pr, Chernogolovka, Moscow Region, 142432, Russia
| | - Sergey G Klochkov
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severny pr, Chernogolovka, Moscow Region, 142432, Russia
| | | | - Cecil E Kirkland
- Department of Biological Sciences, Salem University, Salem, WV, 26426, USA
| | - Gjumrakch Aliev
- Department of Clinical Pathology, Federal State Budgetary Institution "Research Institute of Human Morphology", 3, Tsyurupy Str, Moscow, 117418, Russian Federation.
- I. M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia.
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severny pr, Chernogolovka, Moscow Region, 142432, Russia.
- GALLY International Research Institute, 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA.
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Abstract
For years, clinical and basic researchers have been aware of the presence of PTEN in the nucleus in cell culture, animal models, and both healthy and diseased human tissues. Despite the early recognition of nuclear PTEN, the understanding of the mechanisms of its nuclear localization, function in the nucleus, and importance in biology and human disease has been lacking. Over the last decade, emerging concepts for the complex involvement of nuclear PTEN in a variety of processes, including genome maintenance and DNA repair, cell-cycle control, gene expression, and DNA replication, are illuminating what could prove to be the key path toward a full understanding of PTEN function in health and disease. Dysregulation of nuclear PTEN is now considered an important aspect of the etiology of many pathologic conditions, prompting reconsideration of the therapeutic approaches aimed at countering the consequences of PTEN deficiency. This new knowledge is fueling the development of innovative therapeutic modalities for a broad spectrum of human conditions, from cancer and metabolic diseases, to neurological disorders and autism.
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Affiliation(s)
- Jason Ho
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada
| | - Edward S Cruise
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Ryan J O Dowling
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Vuk Stambolic
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
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40
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Sun Y, Ning X, Fan J, Hu J, Jiang Y, Hu Z, Paulo JA, Liu J, Qiu X, Xu H, Fu S, Gygi SP, Zhang J, Zhou C. Loss of tumor suppressor inositol polyphosphate 4-phosphatase type B impairs DNA double-strand break repair by destabilization of DNA tethering protein Rad50. Cell Death Dis 2020; 11:292. [PMID: 32341333 PMCID: PMC7184567 DOI: 10.1038/s41419-020-2491-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/14/2020] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 12/12/2022]
Abstract
Genome instability is the fundamental hallmark of malignant tumors. Tumor suppressors often play a role in maintaining genome stability. Our previous genetic screen identified inositol polyphosphate 4-phosphatase type B (INPP4B), primarily hydrolyzing phosphatidylinositol 3, 4-disphosphate, is a potential tumor suppressor in lung cancer cells. How INPP4B regulates the genome stability of lung cancer cells is unclear. Here we report knockout of INPP4B in lung adenocarcinoma A549 cells by Crispr-Cas9 gene editing leads to sensitization to ionizing radiation (IR), PARP inhibitor olaparib and impaired DNA homologous recombination repair. Re-introduction of a Crispr-Cas9 resistant INPP4B gene in the INPP4B knockout cells partially restored their resistance to IR, indicating loss of INPP4B protein is relevant to the increased IR sensitivity. Furthermore, we showed ectopic expressed INPP4B in A549 cells responds to IR irradiation by redistribution from cytoplasm to nucleus and endogenous INPP4B protein interacts with Rad50, a crucial MRN complex component for tethering DNA double-strand breaks. Loss of INPP4B protein results in decreased stability of Rad50 in vivo, suggesting an unanticipated role of tumor suppressor INPP4B in maintaining genome integrity via facilitating Rad50 mediated DNA double-strand break repair. Taken together, our findings support a dual role of INPP4B in suppression of tumorigenesis by safeguarding genome stability, as well as inhibiting of PI3K-Akt-mTOR signaling, and offer a new therapeutic strategy for personalized cancer treatment to patients with INPP4B defects or deficiency in the clinic.
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Affiliation(s)
- Yue Sun
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Xuelian Ning
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jiankun Fan
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jiandong Hu
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Yanting Jiang
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Ziqi Hu
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Jichao Liu
- The 2th Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Xiaohong Qiu
- The 2th Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Hui Xu
- The Tumor Hospital, Harbin Medical University, Harbin, 150081, China
| | - Songbin Fu
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Jinwei Zhang
- The 2th Affiliated Hospital, Harbin Medical University, Harbin, 150001, China.
| | - Chunshui Zhou
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China.
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China.
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41
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Huang TT, Lampert EJ, Coots C, Lee JM. Targeting the PI3K pathway and DNA damage response as a therapeutic strategy in ovarian cancer. Cancer Treat Rev 2020; 86:102021. [PMID: 32311593 DOI: 10.1016/j.ctrv.2020.102021] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/12/2020] [Revised: 03/30/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022]
Abstract
Ovarian cancer is the most lethal gynecological malignancy worldwide although exponential progress has been made in its treatment over the last decade. New agents and novel combination treatments are on the horizon. Among many new drugs, a series of PI3K/AKT/mTOR pathway (referred to as the PI3K pathway) inhibitors are under development or already in clinical testing. The PI3K pathway is frequently upregulated in ovarian cancer and activated PI3K signaling contributes to increased cell survival and chemoresistance. However, no significant clinical success has been achieved with the PI3K pathway inhibitor(s) to date, reflecting the complex biology and also highlighting the need for combination treatment strategies. DNA damage repair pathways have been active therapeutic targets in ovarian cancer. Emerging data suggest the PI3K pathway is also involved in DNA replication and genome stability, making DNA damage response (DDR) inhibitors as an attractive combination treatment for PI3K pathway blockades. This review describes an expanded role for the PI3K pathway in the context of DDR and cell cycle regulation. We also present the novel treatment strategies combining PI3K pathway inhibitors with DDR blockades to improve the efficacy of these inhibitors for ovarian cancer.
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Affiliation(s)
- Tzu-Ting Huang
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
| | - Erika J Lampert
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Cynthia Coots
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Jung-Min Lee
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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42
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Abstract
The tumor suppressor phosphatase and tension homolog (PTEN) is frequently mutated in human cancers, and it functions in multiple ways to safeguard cells from tumorigenesis. In the cytoplasm, PTEN antagonizes the PI3K/AKT pathway and suppresses cellular proliferation and survival. In the nucleus, PTEN is indispensable for the maintenance of genomic stability. In addition, PTEN loss leads to extensive changes in gene expression at the transcriptional level. The linker histone H1, generally considered as a transcriptional repressor, binds to the nucleosome to form a structure named the chromatosome. The dynamics between H1 and chromatin play an important role in determining gene expression. Here, we summarize the current understanding of roles of PTEN in controlling chromatin dynamics and global gene expression, which is crucial function of nuclear PTEN. We will also introduce the recent discovery of the PTEN family members and their functions.
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Affiliation(s)
- Jingyi Yang
- Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yuxin Yin
- Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.,Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China
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43
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Cetintas VB, Batada NN. Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment? J Transl Med 2020; 18:45. [PMID: 32000794 PMCID: PMC6993356 DOI: 10.1186/s12967-020-02219-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/06/2019] [Accepted: 01/10/2020] [Indexed: 12/13/2022] Open
Abstract
The PTEN tumor suppressor is the second most commonly inactivated gene across cancer types. While it's role in PI3K/AKT and DNA damage pathways are clear, increasing evidences suggest that PTEN may also promote anti-tumor immunity. PTEN-deficient tumors are characterized by (i) reduced levels of cytotoxic T cells, helper T cells and NK cells, (ii) elevated pro-oncogenic inflammatory cytokines like CCL2 and (iii) increased levels of immunosuppressive cells such as MDSCs and Tregs. An intriguing possibility is that link between PTEN and anti-tumor immunity is mediated by the interferon signaling pathway. In this review, we summarize the evidences for the mechanistic link between PTEN deficiency and immunosuppressive tumor microenvironment and the interferon signaling pathway. We further discuss how the link between these pathways can be exploited for development of personalized immunotherapy for patients with PTEN deficient tumors.
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Affiliation(s)
- Vildan B Cetintas
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey.,Centre for Genomic and Experimental Medicine, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Nizar N Batada
- Centre for Genomic and Experimental Medicine, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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44
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Maidarti M, Anderson RA, Telfer EE. Crosstalk between PTEN/PI3K/Akt Signalling and DNA Damage in the Oocyte: Implications for Primordial Follicle Activation, Oocyte Quality and Ageing. Cells 2020; 9:E200. [PMID: 31947601 PMCID: PMC7016612 DOI: 10.3390/cells9010200] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/31/2019] [Revised: 01/06/2020] [Accepted: 01/13/2020] [Indexed: 12/18/2022] Open
Abstract
The preservation of genome integrity in the mammalian female germline from primordial follicle arrest to activation of growth to oocyte maturation is fundamental to ensure reproductive success. As oocytes are formed before birth and may remain dormant for many years, it is essential that defence mechanisms are monitored and well maintained. The phosphatase and tensin homolog of chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, Akt) is a major signalling pathway governing primordial follicle recruitment and growth. This pathway also contributes to cell growth, survival and metabolism, and to the maintenance of genomic integrity. Accelerated primordial follicle activation through this pathway may result in a compromised DNA damage response (DDR). Additionally, the distinct DDR mechanisms in oocytes may become less efficient with ageing. This review considers DNA damage surveillance mechanisms and their links to the PTEN/PI3K/Akt signalling pathway, impacting on the DDR during growth activation of primordial follicles, and in ovarian ageing. Targeting DDR mechanisms within oocytes may be of value in developing techniques to protect ovaries against chemotherapy and in advancing clinical approaches to regulate primordial follicle activation.
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Affiliation(s)
- Mila Maidarti
- MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (M.M.); (R.A.A.)
- Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3FF, UK
- Obstetrics and Gynaecology Department, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | - Richard A. Anderson
- MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (M.M.); (R.A.A.)
| | - Evelyn E. Telfer
- Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3FF, UK
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45
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Ghayour-Mobarhan M, Ferns GA, Moghbeli M. Genetic and molecular determinants of prostate cancer among Iranian patients: An update. Crit Rev Clin Lab Sci 2020; 57:37-53. [PMID: 31895010 DOI: 10.1080/10408363.2019.1657061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/14/2022]
Abstract
Prostate cancer (PCa) is one of the most common age-related cancers among men. Various environmental and genetic factors are involved in the development and progression of PCa. In most cases, the primary symptoms of disease are not severe. Therefore, it is common for patients to be referred with severe clinical manifestations at advanced stages of disease. Since this malignancy is age related and Iran will face a significant increase in the number of seniors, it is expected that the prevalence of PCa among Iranian men will rise. PCa progression has been observed to be associated with genetic and ethnic factors. It may therefore be clinically useful to determine a panel of genetic markers, in addition to routine diagnostic methods, to detect tumors in the early stages. In the present review, we have summarized the reported genetic markers in PCa Iranian patients to pave the way for the determination of an ethnic specific genetic marker panel for the early detection of PCa. To understand the genetic and molecular biology of PCa among Iranians, we have categorized these genetic markers based on their cellular functions.
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Affiliation(s)
- Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, UK
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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46
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Benstead-Hume G, Wooller SK, Downs JA, Pearl FMG. Defining Signatures of Arm-Wise Copy Number Change and Their Associated Drivers in Kidney Cancers. Int J Mol Sci 2019; 20:E5762. [PMID: 31744086 PMCID: PMC6887958 DOI: 10.3390/ijms20225762] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/19/2019] [Revised: 11/13/2019] [Accepted: 11/14/2019] [Indexed: 01/15/2023] Open
Abstract
Using pan-cancer data from The Cancer Genome Atlas (TCGA), we investigated how patterns in copy number alterations in cancer cells vary both by tissue type and as a function of genetic alteration. We find that patterns in both chromosomal ploidy and individual arm copy number are dependent on tumour type. We highlight for example, the significant losses in chromosome arm 3p and the gain of ploidy in 5q in kidney clear cell renal cell carcinoma tissue samples. We find that specific gene mutations are associated with genome-wide copy number changes. Using signatures derived from non-negative factorisation, we also find gene mutations that are associated with particular patterns of ploidy change. Finally, utilising a set of machine learning classifiers, we successfully predicted the presence of mutated genes in a sample using arm-wise copy number patterns as features. This demonstrates that mutations in specific genes are correlated and may lead to specific patterns of ploidy loss and gain across chromosome arms. Using these same classifiers, we highlight which arms are most predictive of commonly mutated genes in kidney renal clear cell carcinoma (KIRC).
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Affiliation(s)
- Graeme Benstead-Hume
- Bioinformatics Lab, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK; (G.B.-H.); (S.K.W.)
| | - Sarah K. Wooller
- Bioinformatics Lab, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK; (G.B.-H.); (S.K.W.)
| | - Jessica A Downs
- Division of Cancer Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK;
| | - Frances M. G. Pearl
- Bioinformatics Lab, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK; (G.B.-H.); (S.K.W.)
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47
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Chebotarev DA, Makhotkin MA, Naboka AV, Tyutyakina MG, Cherkasova EN, Tarasov VA. Involvement of MicroRNAs in Regulation of Radioresistance of HeLa and DU145 Cells. RUSS J GENET+ 2019. [DOI: 10.1134/s1022795419090047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/23/2022]
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48
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Sun Z, Lu J, Wu M, Li M, Bai L, Shi Z, Hao L, Wu Y. Deficiency of PTEN leads to aberrant chromosome segregation through downregulation of MAD2. Mol Med Rep 2019; 20:4235-4243. [PMID: 31545428 PMCID: PMC6797992 DOI: 10.3892/mmr.2019.10668] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/16/2019] [Accepted: 08/20/2019] [Indexed: 11/07/2022] Open
Abstract
Proper spindle formation and accurate chromosome segregation are essential for ensuring mitotic fidelity. Phosphatase and tensin homolog (PTEN) is a multifunctional protein, which is able to maintain the stability of the genome and chromosomes. The present study described an essential role of PTEN in regulating chromosome segregation to prevent gross genomic instability via regulation of mitotic arrest deficient 2 (MAD2). PTEN knockdown induced cell cycle arrest and abnormal chromosome segregation, which manifested as the formation of anaphase bridges, lagging chromosomes and premature chromatid separation. In addition, MAD2 was identified as a potential target of PTEN. Furthermore, the present study revealed that PTEN knockdown resulted in MAD2 degradation via the ubiquitin-proteasomal pathway, while restoration of MAD2 expression partially ameliorated the mitotic defects induced by PTEN loss. The results from the present study proposed a novel mechanism by which PTEN maintains chromosome stability.
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Affiliation(s)
- Zhuo Sun
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Jinqi Lu
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Muyu Wu
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Mingyan Li
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Lu Bai
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Zhenduo Shi
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China
| | - Lin Hao
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China
| | - Yongping Wu
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
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Multifaceted Regulation of PTEN Subcellular Distributions and Biological Functions. Cancers (Basel) 2019; 11:cancers11091247. [PMID: 31454965 PMCID: PMC6770588 DOI: 10.3390/cancers11091247] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/31/2019] [Revised: 08/15/2019] [Accepted: 08/19/2019] [Indexed: 12/19/2022] Open
Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene frequently found to be inactivated in over 30% of human cancers. PTEN encodes a 54-kDa lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase pathway involved in the promotion of multiple pro-tumorigenic phenotypes. Although the PTEN protein plays a pivotal role in carcinogenesis, cumulative evidence has implicated it as a key signaling molecule in several other diseases as well, such as diabetes, Alzheimer's disease, and autism spectrum disorders. This finding suggests that diverse cell types, especially differentiated cells, express PTEN. At the cellular level, PTEN is widely distributed in all subcellular compartments and organelles. Surprisingly, the cytoplasmic compartment, not the plasma membrane, is the predominant subcellular location of PTEN. More recently, the finding of a secreted 'long' isoform of PTEN and the presence of PTEN in the cell nucleus further revealed unexpected biological functions of this multifaceted molecule. At the regulatory level, PTEN activity, stability, and subcellular distribution are modulated by a fascinating array of post-translational modification events, including phosphorylation, ubiquitination, and sumoylation. Dysregulation of these regulatory mechanisms has been observed in various human diseases. In this review, we provide an up-to-date overview of the knowledge gained in the last decade on how different functional domains of PTEN regulate its biological functions, with special emphasis on its subcellular distribution. This review also highlights the findings of published studies that have reported how mutational alterations in specific PTEN domains can lead to pathogenesis in humans.
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50
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Mechanisms of Genomic Instability in Breast Cancer. Trends Mol Med 2019; 25:595-611. [DOI: 10.1016/j.molmed.2019.04.004] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/05/2019] [Revised: 03/29/2019] [Accepted: 04/04/2019] [Indexed: 12/22/2022]
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