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p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2013 Feb 15; Vol. 267 (1), pp. 113-24. Date of Electronic Publication: 2012 Dec 27. - Publication Year :
- 2013
-
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.<br /> (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Subjects :
- AMP-Activated Protein Kinases physiology
Apoptosis physiology
Autophagy drug effects
Autophagy physiology
Cell Line, Tumor
Humans
Membrane Potential, Mitochondrial drug effects
Membrane Potential, Mitochondrial physiology
Pyrazoles pharmacology
Pyrimidines pharmacology
Skin Neoplasms enzymology
AMP-Activated Protein Kinases antagonists & inhibitors
Apoptosis drug effects
Pyrazoles antagonists & inhibitors
Pyrimidines antagonists & inhibitors
Skin Neoplasms metabolism
Skin Neoplasms pathology
Tumor Suppressor Protein p53 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0333
- Volume :
- 267
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23274516
- Full Text :
- https://doi.org/10.1016/j.taap.2012.12.016