| Title: |
PSMC6 regulation of ovarian cancer cisplatin resistance unravels a new mode for proteasome targeting |
| Authors: |
Costantino, Matteo; Mirra, Luca; D´arcy, Padraig; Corno, Cristina; Carenini, Nives; Corna, Elisabetta; Gubat, Johannes; Ciniselli, Chiara M.; Pratesi, Pietro; Verderio, Paolo; Linder, Stig; Beretta, Giovanni L.; Perego, Paola |
| Publisher Information: |
Linköpings universitet, Avdelningen för klinisk kemi och farmakologi; Linköpings universitet, Medicinska fakulteten; Fdn IRCCS Ist Nazl Tumori, Italy; Karolinska Inst, Sweden; IVYSPRING INT PUBL |
| Publication Year: |
2025 |
| Collection: |
Linköping University Electronic Press (LiU E-Press) |
| Subject Terms: |
ovarian carcinoma; PSMC6; proteasome; cisplatin; drug resistance; DUSP6; Cell and Molecular Biology; Cell- och molekylärbiologi |
| Description: |
Ovarian carcinoma has still a poor prognosis. CRISPR/Cas9 loss-of-function screen revealed a relationship between the PSMC6 proteasome subunit expression and survival of cisplatin-sensitive and -resistant ovarian carcinoma cells. Increased levels of PSMC6 were evidenced in multiple ovarian carcinoma cell lines versus normal cells. An association between PSMC6 levels and tumour stages as well as with a reduced progression-free survival was found. Since a PSMC6 interactome analysis evidenced limited knowledge on PSMC6 biology, mechanistic studies were carried out. PSMC6 knockdown indicated reduced cell growth and clonogenicity in cisplatin-sensitive IGROV-1 and -resistant IGROV-1/Pt1 cells, with a higher impact in resistant cells. This behaviour was accompanied by the accumulation of ubiquitinated proteins and down-regulation of ERK1/2 phosphorylation mediated by increased DUSP6. PSMC6 silencing increased sensitivity to cisplatin in IGROV-1/Pt1 cells as shown by clonogenic assay and 3D spheroids. Since PSMC6 knockdown did not change sensitivity to 20S and 19S proteasome inhibitors, we suggest a new mode of proteasome targeting by interference with a proteasome ATPase. Overall, a link between PSMC6 and ovarian carcinoma aggressiveness is envisioned, highlighting PSMC6 as a potential diagnostic and therapeutic target. ; Funding Agencies|Associazione Italiana per la Ricerca sul Cancro (AIRC IG) [24725]; Italian Ministry of Heath "Ricerca corrente" |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
International Journal of Biological Sciences, 2025, 21:5, s. 2258-2274; PMID 40083690; ISI:001445327700024 |
| DOI: |
10.7150/ijbs.104612 |
| Availability: |
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-212586; https://doi.org/10.7150/ijbs.104612 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.B897BADE |
| Database: |
BASE |