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.
Mol Cancer Ther. 2014 May;13(5):1246-58. doi: 10.1158/1535-7163.MCT-13-0605. Epub 2014 Feb 27.
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.
转移性前列腺癌是致命的，缺乏有效的预防或治疗策略，需要新的治疗方法。白细胞介素-6（IL-6）是一种细胞因子，多项研究表明其与前列腺癌的发病机制有关。然而，IL-6 在前列腺癌生长和进展中的直接功能作用尚不清楚。在本研究中，我们表明 IL-6 存在于临床前列腺癌的远处转移灶中。IL-6 激活的前列腺癌细胞信号通路在裸鼠中诱导了转移形成的强烈 7 倍增加。我们进一步表明，IL-6 促进了迁移性前列腺癌细胞表型，包括增加了前列腺癌细胞的迁移、微管重排和前列腺癌细胞与内皮细胞的异质粘附。IL-6 驱动的转移主要由 Stat3 介导，其次是 ERK1/2。最重要的是，Jak1/2 的药理学抑制 AZD1480 通过抑制 Jak-Stat3 信号通路抑制了 IL-6 诱导的信号、迁移性前列腺癌细胞表型以及裸鼠体内前列腺癌的转移扩散。总之，我们证明了细胞因子 IL-6 通过 Jak-Stat3 信号通路直接促进前列腺癌在体外和体内的转移，并且可以通过使用 Jak1/2 抑制剂 AZD1480 对 Jak1/2 进行药理学靶向来有效抑制 IL-6 驱动的转移。因此，我们的研究结果为进一步开发 Jak1/2 抑制剂作为转移性前列腺癌的治疗方法提供了强有力的依据。
