Pharmacologic suppression of JAK1/2 by JAK1/2 inhibitor AZD1480 potently inhibits IL-6-induced experimental prostate cancer metastases formation.

Abstract

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.

• Authors: Lei Gu, Pooja Talati, Paraskevi Vogiatzi, Ana L Romero-Weaver, Junaid Abdulghani, Zhiyong Liao, Benjamin Leiby, David T Hoang, Tuomas Mirtti, Kalle Alanen, Michael Zinda, Dennis Huszar, Marja T Nevalainen
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 5 Pg. 1246-58 (May 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24577942 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 1480
• Interleukin-6
• Pyrazoles
• Pyrimidines
• STAT3 Transcription Factor
• Janus Kinase 1
• Janus Kinase 2

Topics

• Animals
• Cell Adhesion
• Cell Line, Tumor
• Cell Movement
• Disease Models, Animal
• Gene Expression
• Humans
• Interleukin-6 (genetics, metabolism)
• Janus Kinase 1 (antagonists & inhibitors)
• Janus Kinase 2 (antagonists & inhibitors)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Phenotype
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• STAT3 Transcription Factor (metabolism)