Association of mitochondrial calpain activation with increased expression and autolysis of calpain small subunit in an early stage of apoptosis.

Abstract

Various stimuli including anticancer drugs are capable of initiating the apoptotic death program in human tumor cells via activation of caspases. Mitochondria play an essential role for cell apoptotic commitment. Previous studies have shown a potential role of calpain activation in apoptosis, however, the involved molecular mechanisms remain to be defined. In the current study, we have examined the expression and activation of mitochondrial calpain in Jurkat T leukemia cells, MCF-7 breast carcinoma and LNCaP prostate cancer cells during apoptosis induced by an anticancer drug (VP-16, tamoxifen) or the specific p38 kinase inhibitor PD-169316. Our results suggest that increased expression and autolysis of the mitochondrial calpain small subunit are tightly associated with calpain activation in an early stage of apoptosis. In contrast, there were no correlations observed between the early calpain activation and changes in levels of mitochondrial calpain large subunit and the endogenous calpain inhibitor calpastatin. Furthermore, pretreatment with the specific pharmacological calpain inhibitor calpeptin blocked the drug-induced calpain small subunit autolysis and calpain activation in mitochondria and inhibited apoptosis-associated caspase-3 activation, demonstrating that mitochondrial calpain activation through small subunit cleavage is an essential step for inducing tumor cell apoptosis by various anticancer drugs.

• Authors: Kenyon G Daniel, Johnathan S Anderson, Qing Zhong, Aslamuzzaman Kazi, Puja Gupta, Q Ping Dou
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 12 Issue 2 Pg. 247-52 (Aug 2003) ISSN: 1107-3756 [Print] Greece
• PMID: 12851726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytochrome c Group
• Enzyme Inhibitors
• Imidazoles
• Protein Subunits
• Tamoxifen
• Etoposide
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Calpain
• 2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Autolysis
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Calpain (metabolism)
• Cytochrome c Group (drug effects, metabolism)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Etoposide (pharmacology)
• Female
• Humans
• Imidazoles (pharmacology)
• Jurkat Cells (drug effects)
• Male
• Mitochondria (enzymology, metabolism)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Protein Subunits
• Tamoxifen (pharmacology)
• Tumor Cells, Cultured
• p38 Mitogen-Activated Protein Kinases