Killing cancer cells by targeting glucose metabolism

Cristina Muñoz Pinedo. Cell Death Regulation Group IDIBELL (Institut d'Investigació Biomèdica de Bellvitge)

Oncogenic transformation promotes metabolic changes which makes tumors "addicted" to certain metabolites. For this reason, inhibition of tumor metabolism is a promising new therapeutic approach. However, little is known about how metabolic stress triggers tumor cell death.

Glucose depletion has been shown to kill cells either by necrosis (non-apoptotic, pro-inflamatory cell death) or by the mitochondrial pathway of apoptosis. Our studies indicate that several tumor cell lines of different origins die in a non-apoptotic manner when deprived of glucose. However, we have recently described an atypical apoptotic pathway engaged in cells from solid tumors. Surprisingly, apoptosis induced by glucose deprivation is independent of the Bcl-2-regulated mitochondrial pathway. We will describe this apoptotic pathway mediated by caspase-8, which is the initiator caspase engaged by death receptors of the TNF family.

2-deoxyglucose is a non-metabolizable glucose analog which competes with glucose and has shown anti-tumor effects in animals.
Moreover, this compound is been tested in clinical trials. We are currently studying sensitivity of tumor cells, especially sarcoma cell lines, to 2-deoxyglucose. Interestingly, 2-deoxyglucose promoted apoptosis in cell lines in which glucose deprivation promoted necrosis, suggesting different death mechanisms. 2-deoxyglucose activates the mitochondrial apoptotic pathway and regulates several apoptotic proteins in p53-deficient cells. We found death under normoxia to be associated to endoplasmic reticulum stress rather than lack of ATP. We will discuss the signaling pathways involved in responses to nutritional stress and how to improve sensitivity of tumor cells to metabolic targeting.

Category:

Science & Technology

Tags:

• Killing
• cancer
• cells