BACKGROUND: Neuroendocrine differentiation (NED) is one of the mechanisms underlying development of castration-resistant prostate cancer (CRPC).
In this study, we investigated IL-6-induced NED in two LNCaP sublines.
METHODS: LNCaP-S17, an LNCaP subline that secretes IL-6, and LNCaP-C3, a control subline that does not express IL-6, were analyzed for IL-6-induced NED, activation of JAK2 and STAT3 pathways, and expression of IL-6/IL-6R signaling proteins and downstream target genes.
RESULTS: IL-6 did not induce NED in LNCaP-S17 cells, even though IL-6 induced NED in LNCaP-C3 cells. IL-6 activated JAK2 and STAT3 pathways in LNCaP-C3 cells but not in LNCaP-S17 cells. IL-6 did not activate ERK1/2, AKT, or NF-κB pathways in either cell line. Both LNCaP-C3 and LNCaP-S17 cell lines expressed IL-6R, gp130, and TYK2 at almost the same levels and did not express JAK1 or JAK3. The basal level of JAK2 expression was slightly higher in LNCaP-C3 cells than in LNCaP-S17 cells. Two suppressors of cytokine signaling, SOCS7 and cytokine-inducible SH2 protein (CIS), were expressed constitutively at higher levels in LNCaP-S17 cells than in LNCaP-C3 cells, while SOCS1 to SOCS6 were expressed at approximately the same levels. Using siRNA to knockdown SOCS7 and CIS expression in LNCaP-S17 cells led to increased phosphorylation of STAT3 upon IL-6 stimulation.
CONCLUSIONS: LNCaP-S17 cells are resistant to exogenous IL-6-induced NED due to increased levels of CIS/SOCS7 that block activation of JAK2-STAT3 pathways.
Written by:
Ge D, Gao AC, Zhang Q, Liu S, Xue Y, You Z. Are you the author?
Department of Structural & Cellular Biology, Tulane Cancer Center, Louisiana Cancer Research Consortium, Tulane Center for Aging, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112; Department of Orthopaedic Surgery, Tulane Cancer Center, Louisiana Cancer Research Consortium, Tulane Center for Aging, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112.
Reference: Prostate. 2011 Dec 27.
doi: 10.1002/pros.22479. [Epub ahead of print]
PubMed Abstract
PMID: 22213096
UroToday.com Investigational Urology Section
