title: 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.affiliation: Authors' Affiliations: Departments of Cancer Biology, Urology, and Medical Oncology, Kimmel Cancer Center; Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania; Oncology iMED, AstraZeneca R&D Boston, Waltham, Massachusetts; Department of Pathology, Haartman Institute; Institute of Molecular Medicine, University of Helsinki, Helsinki; and Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.forename: Pooja
authors.initials: P
authors.lastname: Talati
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Vogiatzi
authors.forename: Ana L
authors.initials: AL
authors.lastname: Romero-Weaver
authors.forename: Junaid
authors.initials: J
authors.lastname: Abdulghani
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liao
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leiby
authors.forename: David T
authors.initials: DT
authors.lastname: Hoang
authors.forename: Tuomas
authors.initials: T
authors.lastname: Mirtti
authors.forename: Kalle
authors.initials: K
authors.lastname: Alanen
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.forename: Marja T
authors.initials: MT
authors.lastname: Nevalainen
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C545606:AZD 1480; D015850:Interleukin-6; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D053613:Janus Kinase 1; D053614:Janus Kinase 2