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

Authors

Lei Gu, Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107Follow
Pooja Talati, Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107Follow
Paraskevi Vogiatzi, Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.Follow
Ana L Romero-Weaver, Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107Follow
Junaid Abdulghani, Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107Follow
Zhiyong Liao, Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.Follow
Benjamin E. Leiby, Thomas Jefferson University HospitalFollow
David T. Hoang, Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107Follow
Tuomas Mirtti, Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland.Follow
Kalle Alanen, Dept. of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland.Follow
Michael Zinda, AstraZeneca R&D Boston, Waltham, MA 02451, USA
Dennis Huszar, AstraZeneca R&D Boston, Waltham, MA 02451, USA
Marja T. Nevalainen, Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107Follow

Document Type

Presentation

Publication Date

5-1-2014

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Molecular Cancer Therapeutics

Volume 13, Issue 5, May 2014, Pages 1246-58.

The published version is available at DOI: 10.1158/1535-7163.MCT-13-0605. Copyright ©

American Association for Cancer Research

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.

Recommended Citation

Gu, Lei; Talati, Pooja; Vogiatzi, Paraskevi; Romero-Weaver, Ana L; Abdulghani, Junaid; Liao, Zhiyong; Leiby, Benjamin E.; Hoang, David T.; Mirtti, Tuomas; Alanen, Kalle; Zinda, Michael; Huszar, Dennis; and Nevalainen, Marja T., "Pharmacologic suppression of JAK1/2 by JAK1/2 inhibitor AZD1480 potently inhibits IL-6-induced experimental prostate cancer metastases formation." (2014). Department of Medical Oncology Faculty Papers. Paper 40.
https://jdc.jefferson.edu/medoncfp/40

PubMed ID

24577942