WP1130 increases cisplatin sensitivity through inhibition of usp9x in estrogen receptor-negative breast cancer cells

Approximately 30% of all breast cancers are caused by a lack of estrogen receptor (ER), which renders the cancer resistant to endocrine-based therapy. Many studies suggest that ubiquitin-specific peptidase 9, X-linked (usp9x) regulates multiple cellular behaviors, such as tumor growth, invasion, and resistance to chemotherapeutic agents. This study aimed to evaluate the anti-tumor effects of WP1130, a partially selective inhibitor of deubiquitinating enzymes, in breast cancer cells. We found that WP1130 enhanced cisplatin cytotoxicity in ER-negative tumor cells (MDA-MB-231 and MDA-MB-468), but had little effect in ER-positive Bcap-37 cells. Western blot analysis revealed that usp9x expression was dramatically lower in ER-positive cells compared to that in ER-negative cells. Furthermore, WP1130 treatment suppressed the expression of usp9x and Mcl-1 in ER-negative cells, but not in ER-positive cells. In addition, we found that knockdown of usp9x diminished the chemosensitization activity of WP1130 on breast cancer cells in the presence of cisplatin. Taken together, these results demonstrated that combined treatment with WP1130 could increase the cisplatin sensitivity in a usp9x-dependent manner in estrogen receptor-negative breast cancer cells.