| Title: |
The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis |
| Authors: |
Corno, Cristina; D’Arcy, Padraig; Bagnoli, Marina; Paolini, Biagio; Costantino, Matteo; Carenini, Nives; Corna, Elisabetta; Alberti, Paola; Mezzanzanica, Delia; Colombo, Diego; Linder, Stig; Arrighetti, Noemi; Perego, Paola |
| Contributors: |
C. Corno; P. D’Arcy; M. Bagnoli; B. Paolini; M. Costantino; N. Carenini; E. Corna; P. Alberti; D. Mezzanzanica; D. Colombo; S. Linder; N. Arrighetti; P. Perego |
| Publisher Information: |
Frontiers Media S.A. |
| Publication Year: |
2022 |
| Collection: |
The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| Subject Terms: |
ovarian cancer; ubiquitin-specific protease 8; cisplatin; drug resistance; apoptosis; Settore BIO/10 - Biochimica |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/wos/WOS:000903869400001; volume:10; firstpage:1; lastpage:17; numberofpages:17; journal:FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY; https://hdl.handle.net/2434/948791 |
| DOI: |
10.3389/fcell.2022.1055067 |
| Availability: |
https://hdl.handle.net/2434/948791; https://doi.org/10.3389/fcell.2022.1055067 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.A103E7C1 |
| Database: |
BASE |