Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University (Third Military Medical University), Chongqing, China.
Institute of Combined Injury, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China.
Mol Carcinog. 2018 Sep;57(9):1213-1222. doi: 10.1002/mc.22837. Epub 2018 Jun 12.
The BH3 mimetic (-)-gossypol (-)-G has shown promising efficacy to kill several kinds of cancer cells or potentiate current chemotherapeutics. But it induces limited apoptosis in cancer cells with high level of Bcl-2. The nuclear receptor PPARγ and its agonist rosiglitazone can suppress various malignancies. More importantly, rosiglitazone is able to enhance the anti-tumor effects of chemotherapy drugs such as carboplatin and tyrosine kinase inhibitors. In this study, we for the first time demonstrated that rosiglitazone could sensitize (-)-G to induce apoptosis in cancer cells with high level of Bcl-2. Furthermore, we found that (-)-G increased the mRNA level and protein stability of Mcl-1, which weakened the pro-apoptotic effect of (-)-G. Rosiglitazone attenuated the (-)-G-induced Mcl-1 stability through decreasing JNK phosphorylation. Additionally, rosiglitazone upregulated dual-specificity phosphatase 16 (DUSP16), leading to a reduction of (-)-G-triggered JNK phosphorylation. Animal experiments showed that rosiglitazone could sensitize (-)-G to repress the growth of cancer cells with high level of Bcl-2 in vivo. Taken together, our results suggest that the PPARγ agonists may enhance the therapeutic effect of BH3 mimetics in cancers with high level of Bcl-2 through regulating the DUSP16/JNK/Mcl-1 singling pathway. This study may provide novel insights into the cancer therapeutics based on the combination of PPARγ agonists and BH3 mimetics.
BH3 模拟物 (-)-gossypol (-)-G 已显示出对杀死多种癌细胞或增强当前化疗药物的疗效有很大的潜力。但是，它在高水平 Bcl-2 的癌细胞中诱导的凋亡有限。核受体 PPARγ 及其激动剂罗格列酮可以抑制多种恶性肿瘤。更重要的是，罗格列酮能够增强化疗药物如卡铂和酪氨酸激酶抑制剂的抗肿瘤作用。在这项研究中，我们首次证明罗格列酮能够使 (-)-G 敏感，从而诱导高水平 Bcl-2 的癌细胞发生凋亡。此外，我们发现 (-)-G 增加了 Mcl-1 的 mRNA 水平和蛋白稳定性，这削弱了 (-)-G 的促凋亡作用。罗格列酮通过降低 JNK 磷酸化来减弱 (-)-G 诱导的 Mcl-1 稳定性。此外，罗格列酮上调了双特异性磷酸酶 16（DUSP16），导致 (-)-G 触发的 JNK 磷酸化减少。动物实验表明，罗格列酮可以使 (-)-G 敏感，从而抑制体内高水平 Bcl-2 的癌细胞生长。综上所述，我们的研究结果表明，PPARγ 激动剂可能通过调节 DUSP16/JNK/Mcl-1 信号通路增强高水平 Bcl-2 癌症中 BH3 模拟物的治疗效果。这项研究可能为基于 PPARγ 激动剂和 BH3 模拟物联合的癌症治疗提供新的思路。
