Abstract
ABSTRACTMDM2 antagonists stabilize and activate wild-type p53, and histone methyltransferase (HMT) inhibitors reduce methylation on histone lysines and arginines. Both MDM2 antagonists and HMT inhibitors are being developed as cancer therapeutics. Wild-type p53 expressing HCT116 colon cancer cells were resistant to apoptosis in response to the MDM2 antagonist Nutlin-3a. However, co-treatment with the HMT inhibitor DZNep sensitized the cells to Nutlin-3a-induced apoptosis. This sensitization resulted from reduced activity of the Bcl-2 gene promoter and a reduction in Bcl-2 mRNA and protein. Surprisingly, DZNep reduced Bcl-2 expression in other colon cancer cell lines (RKO, SW48, and LoVo) but failed to sensitize them to Nutlin-3a. We found these cell lines express elevated levels of Bcl-2 or other Bcl-2-family proteins, including Bcl-xL, Mcl-1, and Bcl-w. Knockdown of Mcl-1 and/or treatment with specific or pan Bcl-2-family inhibitors (BH3 mimetics) sensitized RKO, SW48, and LoVo cells to apoptosis by Nutlin-3a. The results demonstrate 1) DZNep represses the Bcl-2 gene promoter and affects apoptosis sensitivity by reducing Bcl-2 protein expression, and 2) elevated expression of pro-survival Bcl-2 family members protects colon cancer cells from Nutlin-3a-induced apoptosis. Targeting Bcl-2 proteins via DZNep or BH3 mimetics could increase the therapeutic potential of MDM2-antagonists like Nutlin-3a in colon cancer.
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