Tan Haiyan, Zeng Chun, Xie Junbo, Alghamdi Norah J, Song Ya, Zhang Hongbing, Zhou Aimin, Jin Di
Clinical Chemistry Program, Department of Chemistry, Cleveland State University, Cleveland, OH, USA.
College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China.
Oncotarget. 2015 Nov 17;6(36):39184-95. doi: 10.18632/oncotarget.5508.
Prostate cancer is the second most commonly diagnosed cancer among men in the United States. Prostate cancer therapy is severely hampered by lack of response and development of resistance to conventional chemotherapeutic drugs in patients. Therefore, the development and discovery of new drugs have become an urgent clinical need. Interferons (IFNs), a family of pleiotropic cytokines, exert antitumor activities due to their anti-proliferative, immunomodulatory and proapoptotic functions. Here, we report that pretreatment of prostate cancer PC-3 cells with IFNs sensitized these cells to double-stranded RNAs (dsRNAs)-induced apoptosis. The enhancement effect of IFN treatment was dependent on IFN subtypes, in particular, IFN γ. In comparison with IFN α or β, IFN γ treatment remarkably augmented apoptosis in PC-3 cells induced with polyinosinic:polycytidylic acid (poly I:C), a synthesized form of dsRNA. We demonstrated that IFN-signaling was necessary for these effects by using mutant cell lines. Transfection of 2-5A, the activator of RNase L, or silencing of dsRNA-dependent protein kinase R (PKR) by siRNA did not have any significant impact on this event, suggesting that neither RNase L nor PKR was involved in poly I:C/IFN γ-induced apoptosis in the cells. Further investigation of the apoptotic pathway revealed that Bak, a pro-apoptotic member of the Bcl-2family, was synergistically up-regulated by IFN γ and poly I:C, whereas other members of the family were not affected. Knocking down of Bak demonstrated its contribution to poly I:C/IFN γ-induced apoptosis in the cells. We believeour findings will precipitate the design of novel therapeutic strategies for prostate cancer.
前列腺癌是美国男性中第二大最常被诊断出的癌症。前列腺癌治疗因患者对传统化疗药物缺乏反应以及产生耐药性而受到严重阻碍。因此,新药的研发已成为迫切的临床需求。干扰素(IFNs)是一类多效性细胞因子,因其具有抗增殖、免疫调节和促凋亡功能而发挥抗肿瘤活性。在此,我们报告用干扰素预处理前列腺癌PC-3细胞可使这些细胞对双链RNA(dsRNAs)诱导的凋亡敏感。干扰素治疗的增强作用取决于干扰素亚型,尤其是干扰素γ。与干扰素α或β相比,干扰素γ治疗显著增强了由聚肌苷酸:聚胞苷酸(poly I:C,一种合成形式的dsRNA)诱导的PC-3细胞凋亡。我们通过使用突变细胞系证明干扰素信号传导对这些效应是必需的。转染核糖核酸酶L的激活剂2-5A或用小干扰RNA沉默双链RNA依赖性蛋白激酶R(PKR)对这一事件没有任何显著影响,这表明核糖核酸酶L和PKR均未参与细胞中聚肌苷酸:聚胞苷酸/干扰素γ诱导的凋亡。对凋亡途径的进一步研究表明,Bak是Bcl-2家族的促凋亡成员,它被干扰素γ和聚肌苷酸:聚胞苷酸协同上调,而该家族的其他成员未受影响。敲低Bak证明了其对细胞中聚肌苷酸:聚胞苷酸/干扰素γ诱导的凋亡的作用。我们相信我们的发现将推动前列腺癌新型治疗策略的设计。