VCP/p97 inhibition disrupts proteostasis and enhances NEDL2 and ubiquitin accumulation in bladder cancer cells
FEBS OPEN BIO, cilt.16, sa.supplement, ss.22, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 16 Sayı: supplement
- Basım Tarihi: 2026
- Doi Numarası: 10.1002/2211-5463.702-05
- Dergi Adı: FEBS OPEN BIO
- Derginin Tarandığı İndeksler: Applied Science & Technology Source, Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Scopus, Science Citation Index Expanded (SCI-EXPANDED), BIOSIS, Chemical Abstracts Core, EMBASE, MEDLINE, Directory of Open Access Journals
- Sayfa Sayıları: ss.22
- Ankara Yıldırım Beyazıt Üniversitesi Adresli: Evet
Özet
Introduction and Rationale: Bladder cancer remains a major clinical challenge due to its high recurrence and resistance to conventional treatments. A key vulnerability of cancer cells is their reliance on tightly regulated protein homeostasis, maintained through the ubiquitin–proteasome system (UPS) and endoplasmic reticulum-associated degradation (ERAD). Valosin-containing protein (VCP/p97) is central to these pathways and has emerged as a novel target in oncology. However, its role in bladder cancer and the downstream molecular consequences of its inhibition are not fully understood. This study investigates theeffects of VCP inhibition on proteostasis and identifies associate dregulatory changes, including the involvement of NEDL2 andubiquitin accumulation.Methods: HTB-9 and HT-1376 bladder cancer cell lines weretreated with VCP inhibitors CB-5083 and NMS-873. Apoptosiswas assessed using Annexin V/PI staining and caspase-3/7 activa-tion assays. Flow cytometry was used to evaluate cell cycle pro-files and protein expression levels of VCP, NEDL2, andubiquitin. Real-time invasion analysis was performed using thexCELLigence system.Results: Both inhibitors reduced cell viability, triggered apoptosis,and suppressed invasion. CB-5083 caused G1 cell cycle arrest,while NMS-873 induced G2/M arrest, indicating distinct yet con-verging anti-proliferative effects. Flow cytometry revealed thatCB-5083 treatment led to decreased VCP expression, significant upregulation of NEDL2, and marked accumulation of ubiquiti-nated proteins, highlighting impaired proteasomal degradation and a potential stress-induced NEDL2 response.Conclusions: These findings demonstrate that VCP/p97 inhibitioneffectively disrupts proteostasis in bladder cancer cells and induces apoptosis. The upregulation of NEDL2 and accumula-tion of ubiquitinated proteins suggest a novel adaptive responseto proteotoxic stress. This study identifies NEDL2 as a potentialregulatory player and therapeutic co-target in VCP-inhibited cancer models.