The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis

The identification of therapeutic approaches to improve response to platinum-
based therapies is an urgent need for ovarian carcinoma. Deubiquitinases are a
large family of ubiquitin proteases implicated in a variety of cellular functions
and may contribute to tumor aggressive features through regulation of
processes such as proliferation and cell death. Among the subfamily of
ubiquitin-specific peptidases, USP8 appears to be involved in modulation of
cancer cell survival by still poorly understood mechanisms. Thus, we used
ovarian carcinoma cells of different histotypes, including cisplatin-resistant
variants with increased survival features to evaluate the efficacy of molecular
targeting of USP8 as a strategy to overcome drug resistance/modulate cisplatin
response. We performed biochemical analysis of USP8 activity in pairs of
cisplatin-sensitive and -resistant cells and found increased USP8 activity in
resistant cells. Silencing of USP8 resulted in decreased activation of receptor
tyrosine kinases and increased sensitivity to cisplatin in IGROV-1/Pt1 resistant
cells as shown by colony forming assay. Increased cisplatin sensitivity was
associated with enhanced cisplatin-induced caspase 3/7 activation and
apoptosis, a phenotype also observed in cisplatin sensitive cells. Increased
apoptosis was linked to FLIP L decrease and cisplatin induction of caspase 3
in IGROV-1/Pt1 cells, cisplatin-induced claspin and survivin down-regulation in
IGROV-1 cells, thereby showing a decrease of anti-apoptotic proteins.
Immunohistochemical staining on 65 clinical specimens from advanced
stage ovarian carcinoma indicated that 40% of tumors were USP8 positive
suggesting that USP8 is an independent prognostic factor for adverse outcome
when considering progression free survival as a clinical end-point. Taken
together, our results support that USP8 may be of diagnostic value and may
provide a therapeutic target to improve the efficacy of platinum-based therapy
in ovarian carcinoma.