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.
Yan
Biao
B
Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Tongji University, Shanghai 200092, China. yanbiao1982@hotmail.com
Kong
Men
M
Chen
Shi
S
Chen
Yi-han
YH
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000378:metabolism; D017209:Apoptosis; D018797:Cell Cycle Proteins; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases