title: How does oncogene transformation render tumor cells hypersensitive to nutrient deprivation?
abstract: Oncogene activation leads to cellular transformation by deregulation of biological processes such as proliferation and metabolism. Paradoxically, this can also sensitize cells to nutrient deprivation, potentially representing an Achilles' heel in early stage tumors. The mechanisms underlying this phenotype include loss of energetic and redox homeostasis as a result of metabolic reprogramming, favoring synthesis of macromolecules. Moreover, an emerging mechanism involving the deregulation of mRNA translation elongation through inhibition of eukaryotic elongation factor 2 kinase (eEF2K) is presented. The potential consequences of eEF2K deregulation leading to cell death under nutrient depletion are discussed. Finally, the relevance of eEF2K as a master regulator of the response to nutrient deprivation in vivo, and its potential exploitation for therapeutic targeting of cancers, are elaborated. Overall, a better understanding of the adaptive mechanisms allowing tumors to circumvent oncogene-induced hypersensitivity to nutrient deprivation is a promising avenue for uncovering novel therapeutic targets in cancers.
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Leprivier
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
mesh_terms: D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D010441:Peptide Chain Elongation, Translational / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C517689:EEF2K protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D054736:Elongation Factor 2 Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: eEF2 kinase (eEF2K); mRNA translation elongation; metabolic stress; oncogenes; stress signaling