TRAINERS PI  Cristina Muñoz-Pinedo and ESR Franziska Püschel have shown that stress triggered by glucose deprivation promotes the ATF4-dependent upregulation of TRAIL-R2/DR5 and TRAIL receptor-mediated cell death. The work was published in the journal “Molecular and Cellular Biology” and an image from their study made the front cover of the journal.

The study investigates how nutrient deprivation triggers an endoplasmic reticulum (ER) stress response and cell death. They show that ATF4 is required for apoptosis induced by glucose deprivation in cells in which caspase-8 is the apoptosis-initiating caspase. Glucose deprivation induces the TRAIL receptors DR4 and DR5. DR5 is regulated by ATF4 in this context, and both receptors mediate cell death, with DR5 being quantitatively more important. These data indicate that stress triggered by glucose deprivation promotes the ATF4-mediated apoptosis  through TRAIL death receptors.

This work is important because cancer cells display glucose avidity and are more sensitive to cell death by starvation than nontransformed cells.  Increasing our understanding in this area may help to develop new strategies to kill cancer cells.