Apoptosis signaling pathways mediated by cyclooxygenase-2 inhibitors in prostate cancer cells

The present study demonstrates that despite similarities in structure and IC50 in COX-2 inhibition, COX-2 inhibitors exhibit vastly different potencies in inducing apoptosis in prostate cancer cells. This discrepancy is attributable to differences in the underlying signaling mechanisms. Our data show that celecoxib triggers rapid apoptotic death of prostate cancer cells by interfering with multiple signaling components essential to cell survival and Ca2+ regulation. The mechanism underlying the concurrent down-regulation of Akt and ERK2 by celecoxib warrants investigation since these two kinases are under regulation by different pathways. In addition, celecoxib stimulates intracellular Ca2+ increase by blocking the ATPdependent Ca2+ re-uptake into internal stores. Thus, celecoxib represents a unique pharmacological tool to study the apoptosis regulation in prostate cancer cells considering its ability to interact with plural targets. Moreover, evidence is mounting that the apoptosis-inducing effect of celecoxib may be dissociated from the COX-2 inhibitory activity. From a clinical perspective, separation of the apoptosis-inducing effect of celecoxib from the COX-2 inhibitory activity may lead to the design of a new class of therapeutic agents against prostate cancer, which represents the current focus of this laboratory.