Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer

• Published in: PloS one Vol. 11; no. 10; p. e0165385
• Main Authors: Fedoseienko, Alina, Wieringa, Hylke W, Wisman, G Bea A, Duiker, Evelien, Reyners, Anna K L, Hofker, Marten H, van der Zee, Ate G J, van de Sluis, Bart, van Vugt, Marcel A T M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.10.2016; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Apoptosis; Apoptosis - drug effects; B cells; Biology and Life Sciences; BRCA1 protein; Breast cancer; Cancer; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Cohort Studies; Copper; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA repair; Female; G2 Phase Cell Cycle Checkpoints - drug effects; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gynecology; Humans; Kinases; Lymphoma; Lymphomas; M Phase Cell Cycle Checkpoints - drug effects; Medical research; Medicine and Health Sciences; Metabolism; Neoplasm Grading; Neoplasm Staging; Oncology; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Patients; Pediatrics; Phosphatase; Platinum; Protein turnover; Proteins; Repair; Research and Analysis Methods; Sensitivity; Sensitivity analysis; Sensitizing; Toxicity; Tumor cell lines; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165385

Copper metabolism MURR1 domain 1 (COMMD1) protein is a multifunctional protein, and its expression has been correlated with patients' survival in different types of cancer. In vitro studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC) patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G2/M checkpoint, and decreased protein expression of the DNA repair gene BRCA1, and the apoptosis inhibitor BCL2. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs), representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; P = 0.038), although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G2/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis.