title: Metabolic catastrophe as a means to cancer cell death.
abstract: During tumorigenesis, normal growth mechanisms are deregulated and safeguards that eliminate abnormal cells by apoptosis are disabled. Tumor cells must also increase nutrient uptake and angiogenesis to support the upregulation of metabolism necessary for unrestricted growth. In addition, they have to rely on inefficient energy production by glycolysis. This glycolytic state can result from mutations that promote cell proliferation, the hypoxic tumor microenvironment and perhaps mitochondrial malfunction. Moreover, the very signals that enable unrestricted cell proliferation inhibit autophagy, which normally sustains cells during nutrient limitation. In tumors, inactivation of the autophagy pathway may enhance necrosis and inflammation and promote genomic instability, which can further enhance tumor growth. Thus, tumor cells cannot adapt efficiently to metabolic stress and could be induced to die by metabolic catastrophe, in which high energy demand is contrasted by insufficient energy production. Efforts to exploit this unique metabolic state clinically previously focused mainly on detecting tissue displaying increased glycolytic metabolism. The challenge now is to induce metabolic catastrophe therapeutically as an approach to killing the unkillable cells.
authors.affiliation: Department of Pharmacology, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Shengkan
authors.initials: S
authors.lastname: Jin
authors.forename: Robert S
authors.initials: RS
authors.lastname: DiPaola
authors.forename: Robin
authors.initials: R
authors.lastname: Mathew
authors.forename: Eileen
authors.initials: E
authors.lastname: White
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071186:Beclin-1; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008954:Models, Biological; D009336:Necrosis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose