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

Abstract

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 FLIPL 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.

The pro-tumorigenic cytokine IL-32 has a high turnover in multiple myeloma cells due to proteolysis regulated by oxygen-sensing cysteine dioxygenase and deubiquitinating enzymes

“…IL-32 is highly expressed by activated T cells (35)(36)(37)(38). DUBs are currently as therapeutic targets in different cancers (23,(39)(40)(41), but they may also influence the cancer microenvironment, including T cells (42). Our data show that the use of proteasome inhibitors and DUB inhibitors affects IL-32 protein levels in T cells, which should be kept in mind when using DUB inhibitors in cancer treatments.…”

Ubiquitin-Specific Proteases as Potential Therapeutic Targets in Bladder Cancer—In Vitro Evaluation of Degrasyn and PR-619 Activity Using Human and Canine Models

“…Anti-apoptotic effect of PR-619 was less pronounced. Prior research has shown that inhibition of USP can induce cell death via caspase-dependent apoptosis [ 16 ]. The activation of effector caspases 3/7, which are proteases responsible for protein cleavage, DNA condensation, and other apoptotic markers, is one of the critical steps during the process [ 17 ].…”

Cellular Functions of Deubiquitinating Enzymes in Ovarian Adenocarcinoma

“…Firstly, we summarized only DUBs with their known substrates in ovarian cancers. There are more studies on identifying important DUBs such as USP8 and USP19 in ovarian cancers [ 173 , 174 ]. However, in this paper, we could not include them, as their target substrates and underlying mechanism were unknown.…”