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Interleukin‐6 induced overexpression of valosin‐containing protein (VCP)/p97 is associated with androgen‐independent prostate cancer (AIPC) progression
Author(s) -
Duscharla Divya,
Reddy Kami Reddy Karthik,
Dasari Chandrashekhar,
Bhukya Supriya,
Ummanni Ramesh
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26639
Subject(s) - lncap , prostate cancer , cancer research , apoptosis , androgen deprivation therapy , androgen receptor , cell , cell growth , downregulation and upregulation , stat3 , microbiology and biotechnology , cancer , biology , chemistry , signal transduction , medicine , biochemistry , gene
Though Androgen deprivation therapy (ADT) is effective initially, numerous patients become resistant to it and develop castration resistant PCa (CRPC). Cytokines promotes ligand independent activation of AR. Interleukin‐6 (IL‐6) levels are elevated in CRPC patients and regulate AR activity. However, progression to CRPC is not fully understood. In this study, we analyzed differential protein expression in LNCaP cells treated with IL‐6 using proteomics. Results revealed altered expression of 27 proteins and Valosin‐containing protein (VCP)/p97 plays a predominant role in co‐regulation of altered proteins. Interestingly, IL‐6 induced VCP expression through Pim‐1 via STAT3 is AR independent there by suggesting a role for VCP in CRPC. Transfection of LNCaP cells for VCP overexpression showed an increased cell proliferation, migration, and invasion where as its inhibition by NMS‐873 showed the reverse effect causing cell death. Mechanistic studies demonstrate that cell death occurs due to apoptosis by endoplasmic reticulum (ER) stress, elevated cell cycle inhibitors p21, p27kip1, and active PARP and reduced Bcl‐2. VCP promotes cell invasion and migration by altering E‐cadherin and Vimentin levels inversely triggering EMT of PCa cells. VCP immunostaining revealed no staining in BPH but strong staining in PCa. This study determines VCP may play an important role in progression to CRPC and it can be a favorable target with to develop new therapies to treat ADT resistant prostate cancer.