Our data suggest that STAT6 is a survival factor in prostate cancer and regulates the genetic transcriptional program that is responsible for prostate cancer progression.

RLIP76 plays a central role in radiation and chemotherapy resistance through its activity as a multispecific ATP-dependent transporter which is over-expressed in a number of types of cancers. RLIP76 appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that depletion or inhibition of RLIP76 causes selective toxicity in malignant cells. RLIP76 induces apoptosis in cancer cells through the accumulation of endogenously formed GS-E. The results of our in vivo studies demonstrate that administration of RLIP76 antibodies, siRNA or anti-sense to mice bearing xenografts of PC-3 prostate cancer cells leads to near complete regression of established subcutaneous xenografts with no apparent toxic effects. Since anti-RLIP76 IgG (which inhibit RLIP76-mediated transport), siRNA and antisense (which deplete RLIP76) showed similar tumor regressing activities, our results indicate that the inhibition of RLIP76 transport activity at the cell surface is sufficient for observed anti-tumor activity. These studies indicate that RLIP76 serves a key effector function for the survival of prostate cancer cells and that it is a valid target for cancer therapy.

RLIP76, a stress-responsive, multi-functional protein with multi-specific transport activity towards glutathione-conjugates (GS-E) and chemotherapeutic agents, is frequently over-expressed in malignant cells. Our recent studies suggest that it plays a prominent anti-apoptotic role selectively in cancer cells. We have previously shown that RLIP76 accounts for up to 80% of the transport of GS-E and blocking the RLIP76-mediated transport of GS-E in cells results in the accumulation of pro-apoptotic endogenous electrophiles and on-set of apoptosis. Here we demonstrate that when RLIP76 mediate transport of GS-E is abrogated either by anti-RLIP76 IgG or accumulation of 4-hydroxynonenal (4-HNE) and its GSH-conjugate (GS-HNE) occurs and a massive apoptosis is observed in cells, indicate that the inhibition of RLIP76 transport activity at the cell surface is sufficient for observed anti-tumor activity. RLIP76 is linked with certain cellular functions including membrane plasticity and movement (as a primary `effector' in the Ral pathway, perhaps functioning as a GTPase activating protein, or GAP), and as a component of clathrin-coated pit-mediated receptor-ligand endocytosis-a process that mediates movement of membrane vesicles.