title: Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer.
abstract: 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.
authors: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Alina
authors: A
authors: Fedoseienko
authors: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Gynecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Hylke W
authors: HW
authors: Wieringa
authors: Department of Gynecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: G Bea A
authors: GB
authors: Wisman
authors: Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Evelien
authors: E
authors: Duiker
authors: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Anna K L
authors: AK
authors: Reyners
authors: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Marten H
authors: MH
authors: Hofker
authors: Department of Gynecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Ate G J
authors: AG
authors: van der Zee
authors: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Bart
authors: B
authors: van de Sluis
authors: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Marcel A T M
authors: MA
authors: van Vugt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; D002945:Cisplatin