title: p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells.
abstract: 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.
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Huang
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Wu
authors.forename: Yen-Ting
authors.initials: YT
authors.lastname: Wang
authors.forename: Jun-Kai
authors.initials: JK
authors.lastname: Kao
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Lin
authors.forename: Chia-Che
authors.initials: CC
authors.lastname: Chang
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Mu
authors.forename: Yu-Yu
authors.initials: YY
authors.lastname: Chen
authors.forename: Husan-Wen
authors.initials: HW
authors.lastname: Chiu
authors.forename: Chuan-Hsun
authors.initials: CH
authors.lastname: Chang
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Liang
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Jau-Ling
authors.initials: JL
authors.lastname: Huang
authors.forename: Jeng-Jer
authors.initials: JJ
authors.lastname: Shieh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011743:Pyrimidines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D012878:Skin Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C516138:dorsomorphin; D055372:AMP-Activated Protein Kinases