VEGF stimulation enhances Livin protein synthesis through mTOR signaling.

Livin is a member of inhibitors of apoptosis proteins (IAPs) and overexpressed in transformed cells and several cancers. Although strategies to decrease Livin levels have been conducted for rational cancer therapy, the molecular mechanism controlling Livin expression in tumors has not been completely elucidated. Here, we show that vascular endothelial growth factor (VEGF) stimulation can increase Livin expression in HeLa cells or SK-MEL-28 cells. This response is independent of de novo gene transcription or changes in mRNA expression but occurs at protein expression levels. VEGF stimulation results in mTOR signaling activation which changes the phosphorylation status of 4E-BP1, the downstream of mTOR signaling, and ultimately contributes to the translation initiation of Livin protein. Livin silencing, Rapamycin alone or in combination with cytotoxic agent can reduce Livin protein levels, and decrease cells viability. Thus, ablation of Livin translation contributes to remove an anti-apoptotic mechanism potentially contributing to aggressive tumor behavior. Pharmacologic inhibition of VEGF/mTOR/Livin signaling may provide a novel strategy for cancer treatment.