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The PPARγ agonist rosiglitazone sensitizes the BH3 mimetic (−)‐gossypol to induce apoptosis in cancer cells with high level of Bcl‐2
Author(s) -
Li Xinzhe,
He Jintao,
Li Bo,
Gao Min,
Zeng Yijun,
Lian Jiqin,
Shi Chunmeng,
Huang Yan,
He Fengtian
Publication year - 2018
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22837
Subject(s) - rosiglitazone , agonist , apoptosis , biology , cancer cell , phosphorylation , cancer research , cancer , downregulation and upregulation , pharmacology , kinase , receptor , endocrinology , microbiology and biotechnology , biochemistry , genetics , gene
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.