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p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells

By Shi-Wei Huang, Chun-Ying Wu, Yen-Ting Wang, Jun-Kai Kao, Chi-Chen Lin, Chia-Che Chang, Szu-Wei Mu, Yu-Yu Chen, Husan-Wen Chiu, Chuan-Hsun Chang, Shu-Mei Liang, Yi-Ju Chen, Jau-Ling Huang and Jeng-Jer Shieh


Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell's p53 status

Topics: Compound C, p53, Apoptosis and autophagy
Year: 2014
DOI identifier: 10.1016/j.taap.2012.12.016
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