| Summary: | 碩士 === 國立臺灣大學 === 藥理學研究所 === 96 === Aberrant DNA hypermethylation is a frequent finding in tumor cells. DNA methyltransferases（DNMTs）inhibitors may reactivate tumor suppressor genes and makes it an effective anticancer strategy. In addition to its demethylating function, DNMT inhibitor, zebularine was also reported to enhance tumor cell radiosensibility. In this study, we found that zebularine induces H2AX phosphorylation through ATR signaling, suggesting the induction of DNA damage by zebularine. Phoshphorylation of p53 at Ser15、overexpression of p53 and p21 proteins and cell cycle G1 arrest were also seen. We assessed the role of an intracellular energy balancing enzyme, AMPK in DNA damage as well. Zebularine activated AMPK, and the inhibition of AMPK by the inhibitor compound C or AMPKα si-RNA resulted in an increase of H2AX phosphorylation and p53 expression. Expression of the constitutive active form of AMPK down-regulated zebularine-induced p53 expression. Our data demostrated that zebularine separately caused DNA damage and activated AMPK. Activation of AMPK may protect the cytotoxic effect of zebularine. Therefore, the combination of zebularine and AMPK inhibitors could be a novel chemotherapeutic strategy.
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