Calcium-Mediated Apoptosis and Apoptotic Sensitization in Prostate Cancer
Abstract
Prostate cancer (PC) cells have limited sensitivity to conventional therapeutic agents due to increased apoptotic thresholds but are highly sensitive to changes in their intracellular calcium levels. This distinction in apoptotic sensitivity may be exploited therapeutically but more information is needed to understand the respective mechanisms and processes involved. In our preliminary studies we identified two potential mediators of calcium-mediated apoptotic sensitization in PC cells. Calcium ionophore treatment of PC cells activated the calciumsensitive protease calpain, stimulating two distinct pathways that regulate phosphotyrosine-initiated cell signaling (PTP1B) or directly trigger apoptosis (caspase 7). The role of caspase 7 and PTP1B in PC cell death and survival signaling was investigated using dominant negatives, siRNA and overexpression of these target proteins. Interference with caspase 7 activation did not appear to effect calcium-mediated cell death and induction of a calpain-proteolyzed variant of PTP1B (tPTP1B) had minimal impact on growth-factor or cytokine-mediated tyrosine phosphorylation or cell survival. Our results suggest that neither caspase 7 nor PTP1B play a major role in prostate cancer sensitivity to calcium-mediated apoptosis or survival signaling through tyrosine phosphorylation. However, due to impact on other kinases (Fak), tPTP1B may limit PC progression and metastatic behavior.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2004
- Accession Number
- ADA485321
Entities
People
- Nicholas J. Donato
Organizations
- The University of Texas MD Anderson Cancer Center