Calcium-Mediated Apoptosis and Apoptotic Sensitization in Prostate Cancer

摘要

Prostate cancer (PC) cells are highly sensitive to changes in their cytoplasmic calcium and this aspect of their biology must be more thoroughly understood to uncover possible new therapeutic targets for this disease. Our preliminary studies demonstrated that calcium activated two pathways that may contribute to the calcium apoptotic sensitivity of PC cells. Calcium mediated activation of calpain results in direct activation of caspase 7 and the tyrosine phosphatase, PTP1B. To study their direct involvement in apoptosis and signaling, PC cells were transfected with dominant negative caspase 7 and inducible constructs of activated PTP1B B. Dominant negative caspase 7 suppressed activation of endogenous caspase 7 by calcium ionophore, supporting a role for its recruitment into the calcium initiated apoptotic process. Activated PTP1B expression (but not a phosphatase-dead mutant) suppressed PC cell growth and blocked signaling through insulin receptor, HER2 and lL-6. However, EGFR signaling was not affected. These data demonstrate that calcium antagonizes specific signal transduction pathways important in PC cells through activation of PTP1B B. Agents that regulate calcium flux and PTP1B activation in PC cells may be active in suppressing PC cells dependent on these signaling pathways for their growth and survival.