Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer

• Published in: Oncotarget 2017-03, Vol.8 (11), p.17700-17711
• Main Authors: Lee, Jong Hyun, Kim, Chulwon, Baek, Seung Ho, Ko, Jeong-Hyeon, Lee, Seok Geun, Yang, Woong Mo, Um, Jae-Young, Sethi, Gautam, Ahn, Kwang Seok
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Enzyme Activation - drug effects; Humans; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - metabolism; Ki-67 Antigen - biosynthesis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness - pathology; Phosphorylation; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Protein Tyrosine Phosphatases - antagonists & inhibitors; Receptor-Like Protein Tyrosine Phosphatases, Class 4 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 4 - metabolism; Research Paper; RNA Interference; RNA, Small Interfering - genetics; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Vanadates - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10775

Persistent STAT3 activation is seen in many tumor cells and promotes malignant transformation. Here, we investigated whether capsazepine (Capz), a synthetic analogue of capsaicin, exerts anticancer effects by inhibiting STAT3 activation in prostate cancer cells. Capz inhibited both constitutive and induced STAT3 activation in human prostate carcinoma cells. Capz also inhibited activation of the upstream kinases JAK1/2 and c-Src. The phosphatase inhibitor pervanadate reversed Capz-induced STAT3 inhibition, indicating that the effect of Capz depends on a protein tyrosine phosphatase. Capz treatment increased PTPε protein and mRNA levels. Moreover, siRNA-mediated knockdown of PTPε reversed the Capz-induced induction of PTPε and inhibition of STAT3 activation, indicating that PTPε is crucial for Capz-dependent STAT3 dephosphorylation. Capz also decreased levels of the protein products of various oncogenes, which in turn inhibited proliferation and invasion and induced apoptosis. Finally, intraperitoneal Capz administration decreased tumor growth in a xenograft mouse prostate cancer model and reduced p-STAT3 and Ki-67 expression. These data suggest that Capz is a novel pharmacological inhibitor of STAT3 activation with several anticancer effects in prostate cancer cells.