Cell death induced by inhibition of glucose metabolism: role of Bcl-2 proteins and autophagy

Nutrient unavailability is associated with pathologies such as cancer, miocardial infarction and stroke. When cells are subjected to acute starvation they may die by apoptosis or necrosis. We are studying the mechanism by which cells die when glucose metabolism is inhibited by employing 2-deoxyglucose (a non-metabolizable glucose analog) or by depriving cells of glucose. In rhabdomyosarcoma cell lines, glucose deprivation induces necrosis, while 2-deoxyglucose induces Noxa-mediated mitochondrial apoptosis. Addition of different carbon/energy sources to 2-deoxyglucose-treated cells indicated that apoptosis is not associated with loss of ATP but rather with endoplasmic reticulum stress and the eIF2-alpha-ATF4 pathway. 2-DG promoted Mcl-1 loss, probably due to general inhibition of translation, since both eIF2-alpha phosphorylation and inactivation of the mTOR pathway were observed.

All these events (ER stress, energetic stress and inhibition of the mTOR pathway) are known to induce autophagy. Indeed, 2-DG induces autophagy, and inhibition of autophagy at different levels sensitizes cells to 2-DG. Surprisingly, this was not the case when cells were challenged by depriving them of glucose. We will present data regarding the role of autophagy in necrotic or apoptotic cell death induced by 2-DG or glucose deprivation.