The Prognostic Significance of the Signaling Proteins: PTEN, P85α, ATM and XIAP in Primary Ovarian Cancer

Background: Cell signaling proteins play a crucial role in tumor behavior. ATM, PTEN, XIAP and p85α are key cell signaling biomarkers. This study evaluates the prognostic significance of those biomarkers in primary Ovarian Cancer (OC). Methods: ATM, PTEN, XIAP and p85α expression was assessed immunohistochemically in a large primary OC cohort (n=525). Outcome analysis was evaluated using progression free and overall survival. Results: High XIAP and p85α expression was associated with features of high-risk OC, including serous histology and higher residual tumor following surgery. P85α negative/low expression improved patients’ platinum sensitivity. Although overexpression of XIAP and p85α was associated with recurrence and poor outcome, upregulated PTEN expression improved outcome. ATM and XIAP were independent prognostic factors in predicting shorter recurrence outcome. In patients with high ATM and XIAP expression, PTEN and p85α lost their significance on patients’ outcome. Conclusion: ATM, PTEN, XIAP and p85α have crucial and different roles in OC progression and can potentially predict patients’ outcome. The data presented here reveal a novel network between the investigated proteins with vital clinical applications in OC. PTEN and p85α are more likely to behave in cell-specific contexts concerning ATM and XIAP expression status.

[1]  C. Marth,et al.  Hopes and failures in front-line ovarian cancer therapy. , 2019, Critical reviews in oncology/hematology.

[2]  D. Oh,et al.  ATM in DNA repair in cancer. , 2019, Pharmacology & therapeutics.

[3]  E. Rakha,et al.  ATM Regulated PTEN Degradation Is XIAP E3 Ubiquitin Ligase Mediated in p85α Deficient Cancer Cells and Influence Platinum Sensitivity , 2019, Cells.

[4]  E. Hirsch,et al.  Targeting PI3K signaling in cancer: Challenges and advances. , 2019, Biochimica et biophysica acta. Reviews on cancer.

[5]  Zhihua Liu,et al.  Inhibition of XIAP increases carboplatin sensitivity in ovarian cancer , 2018, OncoTargets and therapy.

[6]  N. Bowden,et al.  Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment. , 2018, Endocrine-related cancer.

[7]  M. Takano,et al.  Phenoxodiol Increases Cisplatin Sensitivity in Ovarian Clear Cancer Cells Through XIAP Down-regulation and Autophagy Inhibition. , 2018, Anticancer research.

[8]  K. Al-Kuraya,et al.  XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis , 2017, BMC Cancer.

[9]  G. Legube,et al.  Taming Tricky DSBs: ATM on duty. , 2017, DNA repair.

[10]  R. Mohammad,et al.  Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells , 2017, PloS one.

[11]  G. Basso,et al.  Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation , 2016, Leukemia.

[12]  M. O’Connor,et al.  Targeting the DNA Damage Response in Cancer. , 2015, Molecular cell.

[13]  H. Ying,et al.  Expression of NF-κB and PTEN in primary epithelial ovarian carcinoma and the correlation with chemoresistance. , 2015, International journal of clinical and experimental pathology.

[14]  T. Paull.  Mechanisms of ATM Activation. , 2015, Annual review of biochemistry.

[15]  H. Ying,et al.  Chemoresistance is associated with Beclin-1 and PTEN expression in epithelial ovarian cancers , 2015, Oncology letters.

[16]  Y. Zeng,et al.  ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells , 2015, Autophagy.

[17]  G. Ball,et al.  Clinicopathological Significance of ATM-Chk2 Expression in Sporadic Breast Cancers: a Comprehensive Analysis in Large Cohorts , 2014, Neoplasia.

[18]  G. Ball,et al.  ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers , 2014, BBA clinical.

[19]  Wenming Chen,et al.  Significance of p85 expression as a prognostic factor for patients with breast cancer , 2014, Oncology letters.

[20]  Jing Cai,et al.  The role of the PTEN/PI3K/Akt pathway on prognosis in epithelial ovarian cancer: a meta-analysis. , 2014, The oncologist.

[21]  Q. Ji,et al.  Development of Serous Ovarian Cancer is Associated with the Expression of Homologous Recombination Pathway Proteins , 2014, Pathology & Oncology Research.

[22]  C. Rommel,et al.  PI3K and cancer: lessons, challenges and opportunities , 2014, Nature Reviews Drug Discovery.

[23]  Wu-hong Tan,et al.  Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly. , 2013, Acta biochimica et biophysica Sinica.

[24]  Shih-Hsun Chen,et al.  Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies. , 2013, Journal of Clinical Investigation.

[25]  Ji Young Kim,et al.  Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission* , 2013, The Journal of Biological Chemistry.

[26]  C. Seedhouse,et al.  Clinicopathological and functional significance of XRCC1 expression in ovarian cancer , 2013, International journal of cancer.

[27]  H. Yoshikawa,et al.  PIK3CA overexpression is a possible prognostic factor for favorable survival in ovarian clear cell carcinoma. , 2013, Human pathology.

[28]  Y. Shiloh,et al.  The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. , 2013, Nature reviews. Molecular cell biology.

[29]  G. Morelli,et al.  Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells , 2012, Cell Death and Disease.

[30]  P. Pandolfi,et al.  The functions and regulation of the PTEN tumour suppressor , 2012, Nature Reviews Molecular Cell Biology.

[31]  J. Chien,et al.  HtrA1 sensitizes ovarian cancer cells to cisplatin‐induced cytotoxicity by targeting XIAP for degradation , 2012, International journal of cancer.

[32]  Tomasz Milczek,et al.  Selective gene expression profiling of mTOR-associated tumor suppressor and oncogenes in ovarian cancer. , 2011, Folia histochemica et cytobiologica.

[33]  T. Seidal,et al.  Prognostic Impact of Concomitant p53 and PTEN on Outcome in Early Stage (FIGO I-II) Epithelial Ovarian Cancer , 2011, International Journal of Gynecologic Cancer.

[34]  P. Vogt,et al.  Cancer-derived mutations in the regulatory subunit p85α of phosphoinositide 3-kinase function through the catalytic subunit p110α , 2010, Proceedings of the National Academy of Sciences.

[35]  Pascal Meier,et al.  IAPs: from caspase inhibitors to modulators of NF-κB, inflammation and cancer , 2010, Nature Reviews Cancer.

[36]  T. Helleday.  Homologous recombination in cancer development, treatment and development of drug resistance. , 2010, Carcinogenesis.

[37]  M. D. Chamberlain,et al.  Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase , 2010, Proceedings of the National Academy of Sciences.

[38]  L. Languino,et al.  IAP regulation of metastasis. , 2010, Cancer cell.

[39]  B. Peters,et al.  Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. , 2009, Cancer cell.

[40]  Jia-jia Ma,et al.  XIAP gene downregulation by small interfering RNA inhibits proliferation, induces apoptosis, and reverses the cisplatin resistance of ovarian carcinoma. , 2009, European journal of obstetrics, gynecology, and reproductive biology.

[41]  Ping Wang,et al.  Journal of Experimental & Clinical Cancer Research the Drug-resistance to Gefitinib in Pten Low Expression Cancer Cells Is Reversed by Irradiation in Vitro , 2022 .

[42]  J. B. Garrison,et al.  XIAP mediates NOD signaling via interaction with RIP2 , 2009, Proceedings of the National Academy of Sciences.

[43]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[44]  D. Durden,et al.  Regulation of XIAP translation and induction by MDM2 following irradiation. , 2009, Cancer cell.

[45]  Y. Kluger,et al.  Phosphatidylinositol-3-Kinase as a Therapeutic Target in Melanoma , 2009, Clinical Cancer Research.

[46]  A. Tomassetti,et al.  E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells , 2009, Oncogene.

[47]  Yunping Lu 卢运萍,et al.  Correlation between PTEN expression and PI3K/Akt signal pathway in endometrial carcinoma , 2009, Journal of Huazhong University of Science and Technology [Medical Sciences].

[48]  M. Zvelebil,et al.  IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesis , 2008, Nature Cell Biology.

[49]  H. Steller,et al.  Regulation of apoptosis by XIAP ubiquitin-ligase activity. , 2008, Genes & development.

[50]  Da-Qing Yang,et al.  ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells. , 2008, Cellular signalling.

[51]  D. Ma,et al.  [Reversal of drug resistance in human ovarian cancer cells by wild-type PTEN gene and its mechanisms]. , 2007, Zhonghua fu chan ke za zhi.

[52]  Hong Sun,et al.  [Expression of phosphatidylinositol-3 kinase in epithelial ovarian carcinoma]. , 2007, Zhonghua fu chan ke za zhi.

[53]  C. Banwell,et al.  The role of ATM in breast cancer development , 2007, Breast Cancer Research and Treatment.

[54]  H. Nevanlinna,et al.  The CHEK2 gene and inherited breast cancer susceptibility , 2006, Oncogene.

[55]  N. Rahman,et al.  ATM and breast cancer susceptibility , 2006, Oncogene.

[56]  A. Andres-Pons,et al.  Nuclear localization of PTEN by a Ran-dependent mechanism enhances apoptosis: Involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs. , 2006, Molecular biology of the cell.

[57]  Alan Ashworth,et al.  Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. , 2006, Cancer research.

[58]  M. Fraser,et al.  Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner. , 2006, Gynecologic oncology.

[59]  S. Ward,et al.  Phosphatidylinositol 3-kinase mediates activation of ATM by high NaCl and by ionizing radiation: Role in osmoprotective transcriptional regulation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Yufang Tang,et al.  PTEN autoregulates its expression by stabilization of p53 in a phosphatase-independent manner. , 2006, Cancer research.

[61]  M. Loda,et al.  Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[62]  M. D. Chamberlain,et al.  The p85α Subunit of Phosphatidylinositol 3′-Kinase Binds to and Stimulates the GTPase Activity of Rab Proteins* , 2004, Journal of Biological Chemistry.

[63]  Jiri Bartek,et al.  Cell-cycle checkpoints and cancer , 2004, Nature.

[64]  G. Chenevix-Trench,et al.  ATM and Genome Maintenance: Defining Its Role in Breast Cancer Susceptibility , 2004, Journal of Mammary Gland Biology and Neoplasia.

[65]  A. Kimchi,et al.  Autophagy as a cell death and tumor suppressor mechanism , 2004, Oncogene.

[66]  Y. Hashiguchi,et al.  Alteration of cell cycle regulators correlates with survival in epithelial ovarian cancer patients. , 2004, Human pathology.

[67]  Brendan M Leung,et al.  p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells. , 2003, Cancer research.

[68]  Lily Yang,et al.  Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. , 2003, Cancer research.

[69]  P. Oefner,et al.  Contributions of ATM mutations to familial breast and ovarian cancer. , 2003, Cancer research.

[70]  Eric Ogier-Denis,et al.  Autophagy: a barrier or an adaptive response to cancer. , 2003, Biochimica et biophysica acta.

[71]  B. Monia,et al.  PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells , 2002, Oncogene.

[72]  J. Sambrook,et al.  Dominant negative ATM mutations in breast cancer families. , 2002, Journal of the National Cancer Institute.

[73]  R. Abraham.  Cell cycle checkpoint signaling through the ATM and ATR kinases. , 2001, Genes & development.

[74]  G. Mills,et al.  XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. , 2001, Cancer research.

[75]  J. M. Kim,et al.  Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. , 2001, Endocrinology.

[76]  Y. Shiloh,et al.  ATM: genome stability, neuronal development, and cancer cross paths. , 2001, Advances in cancer research.

[77]  B. Vanderhyden,et al.  Human Ovarian Cancer and Cisplatin Resistance: Possible Role of Inhibitor of Apoptosis Proteins* * This work was supported by grants from the Canadian Institutes of Health Research (MOP-15691), the University of Ottawa-Industry Grants Program, and the Ottawa Civic Hospital Foundation. , 2001, Endocrinology.

[78]  Y. Sheng,et al.  Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. , 2000, Cancer research.

[79]  J C Reed,et al.  Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[80]  Y. Nakamura,et al.  Growth suppression of human ovarian cancer cells by adenovirus-mediated transfer of the PTEN gene. , 1999, Cancer research.

[81]  C. Eng,et al.  PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. , 1999, Cancer research.

[82]  J. Dixon,et al.  PTEN: a tumour suppressor that functions as a phospholipid phosphatase. , 1999, Trends in cell biology.

[83]  Joe W. Gray,et al.  PIK3CA is implicated as an oncogene in ovarian cancer , 1999, Nature Genetics.

[84]  A. MacKenzie,et al.  The inhibitors of apoptosis (IAPs) and their emerging role in cancer , 1998, Oncogene.

[85]  K. Mccarty,et al.  Histochemical approaches to steroid receptor analyses. , 1984, Seminars in diagnostic pathology.