Dr. Abelardo López Rivas
Centro Andaluz de Biología Molecular y Medicina Regenerativa, (CABIMER), CSIC
Sevilla, Spain

Host

Dra. Carme Caelles, IRB Barcelona

Friday, 20 June 2008, 12.00h Aula Fèlix Serratosa

Abstract

TRAIL is a ligand of the TNF family capable of inducing apoptosis in a wide variety of cancer cells upon binding to the pro-apoptotic receptors TRAIL-R1 and –R2, but with no effect in the majority of normal human cells tested. Our group is interested on the elucidation of the molecular mechanisms regulating the differential sensitivity of normal and tumor cells to TRAIL-induced apoptosis. Macroautophagy is an evolutionary conserved lysosomal pathway involved in the turnover of cellular macromolecules and organelles. It has an essential role in tissue homeostasis, and defective autophagy is connected to cancer. In spite of this the molecular mechanisms regulating macroautophagy are poorly understood. We have observed that TRAIL induces activation of the AMP-activated protein kinase, inhibits the activity of mammalian target of rapamycin and induces macroautophagy in non-transformed breast epithelial cells. The autophagosome formation is dependent on components of the death-inducing signaling complex, AMP-activated protein kinase and its activator transforming grow th factor-ß-activating kinase 1. Interestingly, transformation by v-H a-Ras or c-Src abrogates TRAIL-induced inhibition of mammalian target of rapamycin and autophagosome formation without affecting caspase 8 processing and activation of the AMP-activated protein kinase. In transformed cells but not in normal epithelial cells, TRAIL activates an apoptotic cell death process.

Thus, transformation-associated changes, downstream of the AMP-activated protein kinase but upstream the mammalian target of rapamycin, prevent TRAIL-induced macroautophagy. We are currently investigating whether autophagy directly prevents apoptosis in non-transformed cells. The autophagy block imposed by transformation might serve as a mechanism whereby the body gets rid of potential dangerous cells with oncogenic mutations.

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