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Rab25 Small GTPase Mediates Secretion of Tumor Necrosis Factor Receptor Superfamily Member 11b (osteoprotegerin) Protecting Cancer Cells from Effects of TRAIL

Cheng KW, Agarwal R, Mitra S and Mills GB

Background: Expression of Rab25, which is located in the 1q amplicon present at high frequency in many cancer lineages, promotes cancer cell survival under multiple stress conditions. While Rab proteins play essential roles in all stages of vesicle trafficking, the functions and endogenous cargoes for Rab25 remain to be fully elucidated. Osteoprotegerin (OPG) is a secreted glycoprotein that binds the tumor necrosis factor-related apoptosisinducing ligand (TRAIL) thus preventing it from activating the TNF-family death receptors. In the present study, we demonstrated that Rab25 regulates OPG at both the transcription and secretion level. Methods: The effect of Rab25 on OPG expression and its effect on TRAIL-induced cell were examined in both ovarian and breast cells. Signal transduction pathways regulation of OPG expression was examined in cells using pharmacogenetic approaches. Results: Expression of Rab25 to levels similar to those in tumors with RAB25 amplification, increased OPG mRNA expression and secretion from ovarian and breast cancer cell lines, whereas down regulation with Rab25 specific siRNA decreased OPG secretion and sensitized cells to TRAIL-induced cell death. Critically, exogenous OPG mimicked the effects of Rab25 on cell death supporting the contention that Rab25-induced accumulation of OPG protects cancer cells from the effects of TRAIL. Rab25 cooperates with EGFR-mediated MAPK signaling to increase TRAIL production and release. Importantly, priming cells with EGFR inhibitors increased sensitivity to TRAIL-induced cells death regardless of the Rab25 background. Conclusion: Increased OPG expression induced by Rab25 may provide a mechanistic advantage for cancer development and progression.