p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China)
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan (China)
- Department of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan (China)
- Institute of Biotechnology, National Cheng-Kung University, Tainan, Taiwan (China)
- Department of Surgical Oncology, Cheng Hsin General Hospital, Taipei, Taiwan (China)
- Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan (China)
- Department of Bioscience Technology, Chang Jung Christian University, Tainan, Taiwan (China)
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. - Highlights: ► Compound C caused more apoptosis in p53 wildtype than p53-mutant skin cancer cells. ► Compound C can upregulate p53 expression and induce p53 activation. ► Compound C induced p53 effects were dependent on ROS induced DNA damage pathway. ► p53-knockdown attenuated compound C-induced apoptosis but not autophagy. ► Compound C-induced apoptosis in skin cancer cells was dependent on p53 status.
- OSTI ID:
- 22285245
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 267, Issue 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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