A Novel Mitochondria-Dependent Apoptotic Pathway (MAP) in Prostate Cancer (Pca) Cells
Abstract
First, I observed that early during apoptosis induction by a wide spectrum of stimuli, there is a prominent mitochondrial activation, which is characterized by increased mitochondrial respiration, electron transport, and upregulation of multiple respiration-related genes, in particular, cytochrome c. This early mitochondrial activation may represent a defensive mechanism against apoptotic stimulation. In support, many mitochondrially-localized, non-respiration proteins with pro-survival functions including HSP60, Bcl-2, and Bcl-X(sub L) are also up-regulated (Chandra et al., J. Biol. Chem., 277, 50842-54; 2002). Later, when the apoptotic machinery is activated, I notice that there is prominent localization of active caspase-9 and -3 in the mitochondria. The accumulated cytochrome c in the mitochondria early during apoptosis raises a possibility that the mitochondrially-localized caspase-9 might be activated in the organelle in an Apaf-1/cytochrome c-dependent manner. My subsequent biochemical characterizations exclude this possibility and show that the majority of the mitochondrially-localized active caspases, including caspase-9 and caspase-3, result from translocation from the cytosol. The resulting mitochondrial active caspases may function as a positive feedback mechanism to further activate other or residual mitochondrial procaspases, degrade mitochondrial constituents, and disintegrate mitochondrial functions (Chandra and Tang, J. Biol. Chem., 278, 17408-20; 2003). Recently, I observed that active caspase-8 also becomes associated with the mitochondria/ER -enriched membranes and caspase-8 activation plays a critical role in initiating etoposide-induced cell death.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2004
- Accession Number
- ADA423414
Entities
People
- Dhyan Chandra
Organizations
- The University of Texas MD Anderson Cancer Center