title: p58(IPK)-mediated attenuation of the proapoptotic PERK-CHOP pathway allows malignant progression upon low glucose.
abstract: As solid tumors expand, oxygen and nutrients become limiting owing to inadequate vascularization and diffusion. How malignant cells cope with this potentially lethal metabolic stress remains poorly understood. We found that glucose shortage associated with malignant progression triggers apoptosis through the endoplasmic reticulum (ER) unfolded protein response (UPR). ER stress is in part caused by reduced glucose flux through the hexosamine pathway. Deletion of the proapoptotic UPR effector CHOP in a mouse model of K-ras(G12V)-induced lung cancer increases tumor incidence, strongly supporting the notion that ER stress serves as a barrier to malignancy. Overcoming this barrier requires the selective attenuation of the PERK-CHOP arm of the UPR by the molecular chaperone p58(IPK). Furthermore, p58(IPK)-mediated adaptive response enables cells to benefit from the protective features of chronic UPR. Altogether, these results show that ER stress activation and p58(IPK) expression control the fate of malignant cells facing glucose shortage.
authors: University of Lyon, 69000 Lyon, France.
authors: Anne-Laure
authors: AL
authors: Huber
authors: Justine
authors: J
authors: Lebeau
authors: Patricia
authors: P
authors: Guillaumot
authors: Virginie
authors: V
authors: Pétrilli
authors: Mouhannad
authors: M
authors: Malek
authors: Julien
authors: J
authors: Chilloux
authors: Frédérique
authors: F
authors: Fauvet
authors: Léa
authors: L
authors: Payen
authors: Alain
authors: A
authors: Kfoury
authors: Toufic
authors: T
authors: Renno
authors: Eric
authors: E
authors: Chevet
authors: Serge N
authors: SN
authors: Manié
mesh_terms: D000116:Acetylgalactosamine / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology; D005947:Glucose / Q000172:deficiency*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000502:physiology*; D009368:Neoplasm Transplantation; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D051381:Rats; D051742:Transcription Factor CHOP / Q000378:metabolism*; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000116:Acetylgalactosamine; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005947:Glucose; D051272:Glucose Transporter Type 1; D006360:Heat-Shock Proteins; D019344:Lactic Acid; D018832:Molecular Chaperones; D051096:Proto-Oncogene Proteins c-ret; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C495679:Slc2a1 protein, rat; C581208:p58(IPK) protein, rat; C495001:Ret protein, rat