Dependence of two forms of cancers on phosphatidyl inositol 3-kinase signal transduction pathways

Survival, growth, proliferation and differentiation are global functions of cellular life. Since cancer progression is similarly dependent on these processes, understanding of molecular mechanisms underlying these functions allows design of targeted therapeutic strategies. Toward this aim, in two models of Cancer, we studied the contribution of the constitutive enzymatic activity of PI-3 Kinase in respect to these parameters.; In Chronic Myelogenous Leukemia, a chromosomal translocation allows expression of an oncogene that in turns decouples intracellular functions from extracellular instructive signals. Expression of the Bcr-Abl oncogene has been shown to constitutively activate a number signal transduction pathways, among them those dependent on PI-3K. Resistance to apoptosis and increased threshold of survival is characteristic of many cancer cells. Accordingly, we investigated the effects of Bcr-Abl expression in modulation of activity of regulators of cellular survival at the mitochondria. We reported that Bad, a pro-apoptotic member of the Bcl-2 family is constitutively inactivated in Bcr-Abl expressing cells through PI-3K and RAS dependent mechanisms. The ability of Bcr-Abl to confer cytokine independent growth and survival was severely compromised in presence of inhibitors of PI-3K as well as dominant negative form of Raf targeted to the mitochondria. Importantly, despite complete block of Bad phosphorylation by a dominant negative form of mitochondrial Raf, a subpopulation of resistant cells were identified and further characterized. We thereby concluded that Bcr-Abl modulates distal nodes in the survival pathway through PI-3K dependent pathways and that inhibition of activity of these regulators as potential therapeutic regiments is hindered by counter selection for complimentary survival mechanisms independent of Bad.; In the Prostate cancer model, the role of PI-3K was primarily investigated in terms of its impact on growth and proliferation. Inactivation of the tumor suppressor PTEN is observed in a large percentage of advanced prostatic cancers. PTEN reverts the action of PI-3K and its inactivation results in deregulated and constitutive activity PI-3K. Much evidence has shown dependence of mTOR, a regulator of cellular growth and survival, as a function of PI-3K activity. (Abstract shortened by UMI.)...