Pharmacologic suppression of JAK1/2 by JAK1/2 inhibitor AZD1480 potently inhibits IL-6-induced experimental prostate cancer metastases formation. Mol Cancer Ther 2014 May;13(5):1246-58
Date
03/01/2014Pubmed ID
24577942Pubmed Central ID
PMC4013199DOI
10.1158/1535-7163.MCT-13-0605Scopus ID
2-s2.0-84899856053 (requires institutional sign-in at Scopus site) 38 CitationsAbstract
Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6-activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6-driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6-induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak-Stat3 signaling pathway, and that IL-6-driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer.
Author List
Gu L, Talati P, Vogiatzi P, Romero-Weaver AL, Abdulghani J, Liao Z, Leiby B, Hoang DT, Mirtti T, Alanen K, Zinda M, Huszar D, Nevalainen MTMESH terms used to index this publication - Major topics in bold
AnimalsCell Adhesion
Cell Line, Tumor
Cell Movement
Disease Models, Animal
Gene Expression
Humans
Interleukin-6
Janus Kinase 1
Janus Kinase 2
MAP Kinase Signaling System
Male
Mice
Mice, Nude
Neoplasm Metastasis
Phenotype
Prostatic Neoplasms
Pyrazoles
Pyrimidines
STAT3 Transcription Factor
