title: Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer.
abstract: 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.
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Baek
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Ko
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Seok Geun
authors.initials: SG
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Woong Mo
authors.initials: WM
authors.lastname: Yang
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Um
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C076715:pervanadate; D014638:Vanadates; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C490825:PTPRE protein, human; D017027:Protein Tyrosine Phosphatases; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; C071423:capsazepine; D002211:Capsaicin
keywords: PTPe; STAT3; apoptosis; capsazepine; prostate cancer