title: Glucose--a sweet way to die: metabolic switching modulates tumor cell death.
abstract: TRAIL, a putative anticancer cytokine, induces extrinsic cell death by activating the caspase cascade directly (Type I cells) via the death-inducing signaling complex (DISC) or indirectly (Type II cells) by caspase-8 cleavage of Bid and activation of the mitochondrial cell death pathway. Cancer cells are characterized by their dependence on aerobic glycolysis, which, although inefficient in terms of ATP production, facilitates tumor metabolism. Our studies show that TRAIL-induced cell death is significantly affected by the metabolic status of the cell. Inhibiting glycolysis with 2-deoxyglucose potentiates TRAIL-induced cell death, whereas glucose deprivation can paradoxically inhibit apoptosis. These conflicting responses to glycolysis inhibition are modulated by the balance between the Akt and AMPK pathways and their subsequent downstream regulation of mTORC1. This results in marked changes in protein translation, in which the equilibrium between anti- and pro-apoptotic Bcl-2 family member proteins is decided by their individual degradation rates. This regulates the mitochondrial cell death pathway and alters its sensitivity not only to TRAIL, but to ABT-737, a Bcl-2 inhibitor. Taken together, our studies show that the sensitivity of cancer cells to apoptosis can be modulated by targeting their unique metabolism in order to enhance sensitivity to apoptotic agents.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK. mm21@le.ac.uk
authors.forename: Marion
authors.initials: M
authors.lastname: MacFarlane
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Robinson
authors.forename: Kelvin
authors.initials: K
authors.lastname: Cain
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology; D003847:Deoxyglucose / Q000633:toxicity; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000633:toxicity*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D046912:Multiprotein Complexes; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; D003847:Deoxyglucose; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose