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Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways.

Valli A, Rodriguez M, Moutsianas L, Fischer R, Fedele V, Huang HL, Van Stiphout R, Jones D, Mccarthy M, Vinaxia M, Igarashi K, Sato M, Soga T, Buffa F, Mccullagh J, Yanes O, Harris A, Kessler B - Oncotarget (2015)

Bottom Line: To study the role of HIF1α in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1α and cells in which the hif1α gene was deleted to characterize HIF1α-dependent and independent effects on hypoxia regulated lipid metabolites.Palmitate, stearate, PLD3 and PAFC16 were regulated in a HIF-independent manner.Our results demonstrate the impact of hypoxia on lipid metabolites, of which a distinct subset is regulated by HIF1α.

View Article: PubMed Central - PubMed

Affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

ABSTRACT
The biochemistry of cancer cells diverges significantly from normal cells as a result of a comprehensive reprogramming of metabolic pathways. A major factor influencing cancer metabolism is hypoxia, which is mediated by HIF1α and HIF2α. HIF1α represents one of the principal regulators of metabolism and energetic balance in cancer cells through its regulation of glycolysis, glycogen synthesis, Krebs cycle and the pentose phosphate shunt. However, less is known about the role of HIF1α in modulating lipid metabolism. Lipids serve cancer cells to provide molecules acting as oncogenic signals, energetic reserve, precursors for new membrane synthesis and to balance redox biological reactions. To study the role of HIF1α in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1α and cells in which the hif1α gene was deleted to characterize HIF1α-dependent and independent effects on hypoxia regulated lipid metabolites. Untargeted metabolomics integrated with proteomics revealed that hypoxia induced many changes in lipids metabolites. Enzymatic steps in fatty acid synthesis and the Kennedy pathway were modified in a HIF1α-dependent fashion. Palmitate, stearate, PLD3 and PAFC16 were regulated in a HIF-independent manner. Our results demonstrate the impact of hypoxia on lipid metabolites, of which a distinct subset is regulated by HIF1α.

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Patterns of adaptation of hypoxic cell metabolismProteo-metabolomics hypoxic response of colorectal cancer cells in normoxia and hypoxia was classified according to two way ANOVA test of significance of the source of variation (HIF1-α, O2 tension and their interaction) and for the statistical significance within the groups after Bonferroni multiple comparisons post-test analysis.
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Figure 2: Patterns of adaptation of hypoxic cell metabolismProteo-metabolomics hypoxic response of colorectal cancer cells in normoxia and hypoxia was classified according to two way ANOVA test of significance of the source of variation (HIF1-α, O2 tension and their interaction) and for the statistical significance within the groups after Bonferroni multiple comparisons post-test analysis.

Mentions: For data analysis purposes, the metabolic effects were classified as shown in a schematic representation (Figure 2): (i) HIF1α-independent response: comparable changes (gain or suppression) were seen in wild type and hif1α−/− cells under hypoxia; (ii) HIF1α-dependent response in hypoxia: changes (gain or suppression) were observed in wild type vs hif1α−/− hypoxic cells only; (iii) HIF1α-dependent response independent of hypoxia: the metabolic response was similarly regulated (gain or suppression) in hif1α−/− vs wild type in normoxic and hypoxic cells; and (iv) HIF1α-dependent and hypoxia-dependent mixed-response: absence of HIF1α (hif1α−/−) caused a regulation (gain or suppression) as compared to wild type cells and hypoxia caused a regulation (gain or suppression) as compared to normoxic cells (Figure 2).


Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways.

Valli A, Rodriguez M, Moutsianas L, Fischer R, Fedele V, Huang HL, Van Stiphout R, Jones D, Mccarthy M, Vinaxia M, Igarashi K, Sato M, Soga T, Buffa F, Mccullagh J, Yanes O, Harris A, Kessler B - Oncotarget (2015)

Patterns of adaptation of hypoxic cell metabolismProteo-metabolomics hypoxic response of colorectal cancer cells in normoxia and hypoxia was classified according to two way ANOVA test of significance of the source of variation (HIF1-α, O2 tension and their interaction) and for the statistical significance within the groups after Bonferroni multiple comparisons post-test analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385826&req=5

Figure 2: Patterns of adaptation of hypoxic cell metabolismProteo-metabolomics hypoxic response of colorectal cancer cells in normoxia and hypoxia was classified according to two way ANOVA test of significance of the source of variation (HIF1-α, O2 tension and their interaction) and for the statistical significance within the groups after Bonferroni multiple comparisons post-test analysis.
Mentions: For data analysis purposes, the metabolic effects were classified as shown in a schematic representation (Figure 2): (i) HIF1α-independent response: comparable changes (gain or suppression) were seen in wild type and hif1α−/− cells under hypoxia; (ii) HIF1α-dependent response in hypoxia: changes (gain or suppression) were observed in wild type vs hif1α−/− hypoxic cells only; (iii) HIF1α-dependent response independent of hypoxia: the metabolic response was similarly regulated (gain or suppression) in hif1α−/− vs wild type in normoxic and hypoxic cells; and (iv) HIF1α-dependent and hypoxia-dependent mixed-response: absence of HIF1α (hif1α−/−) caused a regulation (gain or suppression) as compared to wild type cells and hypoxia caused a regulation (gain or suppression) as compared to normoxic cells (Figure 2).

Bottom Line: To study the role of HIF1α in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1α and cells in which the hif1α gene was deleted to characterize HIF1α-dependent and independent effects on hypoxia regulated lipid metabolites.Palmitate, stearate, PLD3 and PAFC16 were regulated in a HIF-independent manner.Our results demonstrate the impact of hypoxia on lipid metabolites, of which a distinct subset is regulated by HIF1α.

View Article: PubMed Central - PubMed

Affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

ABSTRACT
The biochemistry of cancer cells diverges significantly from normal cells as a result of a comprehensive reprogramming of metabolic pathways. A major factor influencing cancer metabolism is hypoxia, which is mediated by HIF1α and HIF2α. HIF1α represents one of the principal regulators of metabolism and energetic balance in cancer cells through its regulation of glycolysis, glycogen synthesis, Krebs cycle and the pentose phosphate shunt. However, less is known about the role of HIF1α in modulating lipid metabolism. Lipids serve cancer cells to provide molecules acting as oncogenic signals, energetic reserve, precursors for new membrane synthesis and to balance redox biological reactions. To study the role of HIF1α in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1α and cells in which the hif1α gene was deleted to characterize HIF1α-dependent and independent effects on hypoxia regulated lipid metabolites. Untargeted metabolomics integrated with proteomics revealed that hypoxia induced many changes in lipids metabolites. Enzymatic steps in fatty acid synthesis and the Kennedy pathway were modified in a HIF1α-dependent fashion. Palmitate, stearate, PLD3 and PAFC16 were regulated in a HIF-independent manner. Our results demonstrate the impact of hypoxia on lipid metabolites, of which a distinct subset is regulated by HIF1α.

Show MeSH
Related in: MedlinePlus