title: Synthesis of cytochrome C oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death.
abstract: P53 has an important role in the processing of starvation signals. P53-dependent molecular mediators of the Warburg effect reduce glucose consumption and promote mitochondrial function. We therefore hypothesized that the retention of wild-type p53 characteristic of primary glioblastomas limits metabolic demands induced by deregulated signal transduction in the presence of hypoxia and nutrient depletion. Here we report that short hairpin RNA-mediated gene suppression of wild-type p53 or ectopic expression of mutant temperature-sensitive dominant-negative p53(V135A) increased glucose consumption and lactate production, decreased oxygen consumption and enhanced hypoxia-induced cell death in p53 wild-type human glioblastoma cells. Similarly, genetic knockout of p53 in HCT116 colon carcinoma cells resulted in reduced respiration and hypersensitivity towards hypoxia-induced cell death. Further, wild-type p53 gene silencing reduced the expression of synthesis of cytochrome c oxidase 2 (SCO2), an effector necessary for respiratory chain function. An SCO2 transgene reverted the metabolic phenotype and restored resistance towards hypoxia in p53-depleted and p53 mutant glioma cells in a rotenone-sensitive manner, demonstrating that this effect was dependent on intact oxidative phosphorylation. Supplementation with methyl-pyruvate, a mitochondrial substrate, rescued p53 wild-type but not p53 mutant cells from hypoxic cell death, demonstrating a p53-mediated selective aptitude to metabolize mitochondrial substrates. Further, SCO2 gene silencing in p53 wild-type glioma cells sensitized these cells towards hypoxia. Finally, lentiviral gene suppression of SCO2 significantly enhanced tumor necrosis in a subcutaneous HCT116 xenograft tumor model, compatible with impaired energy metabolism in these cells. These findings demonstrate that glioma and colon cancer cells with p53 wild-type status can skew the Warburg effect and thereby reduce their vulnerability towards tumor hypoxia in an SCO2-dependent manner. Targeting SCO2 may therefore represent a valuable strategy to enhance sensitivity towards hypoxia and may complement strategies targeting glucose metabolism.
authors: Dr Senckenberg Institute of Neurooncology, Goethe University Frankfurt, Frankfurt, Germany.
authors: C
authors: C
authors: Wanka
authors: D P
authors: DP
authors: Brucker
authors: O
authors: O
authors: Bähr
authors: M
authors: M
authors: Ronellenfitsch
authors: M
authors: M
authors: Weller
authors: J P
authors: JP
authors: Steinbach
authors: J
authors: J
authors: Rieger
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019069:Cell Respiration; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D024101:Mitochondrial Proteins / Q000502:physiology*; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009336:Necrosis; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; C400285:SCO2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005947:Glucose