Bcl-2 interrupts vincristine-induced apoptosis and arachidonic acid release

Chemotherapeutic agents, including Vincristine (VCR) and Dexmethasnone, have been shown to kill tumor cells by inducing apoptosis (programmed cell death). The overexpression of Bcl-2 protein can prevent cells from apoptosis induced by these Chemotherapeutic agents. However, the signal transduction pathway underlying this phenomenon is still unknown. In these studies, the roles of ceramide, a product of sphingomyelin turnover, and arachidonic acid, the second messenger molecule, are investigated. We show that the proto-oncogene Bcl-2 acts at a point downstream of ceramide generation measured by Diacylglycerol kinase assay, but upstream of phospholipase A2 activation in response to VCR measured by arachidonic acid release. Using inhibitors of the different forms of phospholipase A2, and other criteria, we find that the phospholipase A2 in this signal transduction pathway is not the cPLA2 form of phospholipase A2. The regulation of this phospholipase A2 in response to VCR treatment and by bcl-2 is still under investigation.