The PPARγ agonist rosiglitazone sensitizes the BH3 mimetic (-)-gossypol to induce apoptosis in cancer cells with high level of Bcl-2
The PPARγ agonist rosiglitazone sensitizes the BH3 mimetic (-)-gossypol to induce apoptosis in cancer cells with high level of Bcl-2
复制标题
PPAR γ 激动剂罗格列酮使 BH3 模拟 (-)-棉酚敏感，诱导高水平 Bcl-2 癌细胞凋亡
DOI：
10.1002/mc.22837
复制
发表时间：
2018-09-01
影响因子：
4.6
通讯作者：
He, Fengtian
中科院分区：
文献类型：
--
作者：
Li, Xinzhe;He, Jintao;He, Fengtian
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 PPAR gamma 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 PPAR gamma agonists may enhance the therapeutic effect of BH3 mimetics in cancers with high level of Bcl-2 through regulating the DUSP16/JNK/Mcl-l singling pathway. This study may provide novel insights into the cancer therapeutics based on the combination of PPAR gamma agonists and BH3 mimetics.
