Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer.

Alina Fedoseienko,Hylke W Wieringa,Evelien Duiker,Ate G J Van Der Zee,Marcel A T M Van Vugt,Marten H Hofker,Bart Van De Sluis,G Bea A Wisman,Anna K L Reyners

doi:10.1371/journal.pone.0165385

Alina Fedoseienko, Hylke W Wieringa + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0165385

Copy DOI

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.

Highlights

Copper metabolism MURR1 domain 1 (COMMD1) protein is a small ubiquitously expressed protein, which has been shown to effect tumor cell behavior and survival [1,2,3,4]
We show that increased levels of nuclear COMMD1 affect cisplatin sensitivity in ovarian cancer cells in vitro, and that nuclear COMMD1 expression in ovarian cancer tumor tissue is associated with improved response to cisplatin treatment in one out of two analyzed patient cohorts
To assess the expression of COMMD1 in ovarian tumors, we first determined the specificity of the anti-COMMD1 antibody in HeLa and HEK293T cell lines, which were stable depleted for COMMD1 (Fig 1A and 1B) [1,19]

Summary

Introduction

Copper metabolism MURR1 domain 1 (COMMD1) protein is a small ubiquitously expressed protein, which has been shown to effect tumor cell behavior and survival [1,2,3,4]. One of the proposed mechanisms of COMMD1 in mediating the behavior of cancer involves its inhibitory action on the activity of the transcription factors hypoxia inducible factor 1 (HIF-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [1,4]. COMMD1 represses HIF-1 activity [19,20], and elevated nuclear COMMD1 expression augments its inhibitory effect on both NF-Ф06BB and HIF-mediated transcription [10]. The exact mechanism underlying this effect, and whether COMMD1 expression levels are associated with the response to platinum-based therapy in cancer patients remains unclear

Methods

Results

Conclusion