Hypoxia Induces a Lipogenic Cancer Cell Phenotype Via HIF1α-dependent and -independent Pathways

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Jan 22

PMID 25605240

Citations 42

Authors

Alessandro Valli

Miguel Rodriguez

Loukas Moutsianas

Roman Fischer

Vita Fedele

Hong-Lei Huang

Ruud van Stiphout

Dylan Jones

Michael McCarthy

Maria Vinaxia

Kaori Igarashi

Maya Sato

Tomoyoshi Soga

Francesca Buffa

James McCullagh

Oscar Yanes

Adrian Harris

Benedikt Kessler

Affiliations

Soon will be listed here.

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.

Citing Articles

Tumor hypoxia and role of hypoxia-inducible factor in oral cancer.

Singh P, Rajput M, Pandey M World J Surg Oncol. 2024; 22(1):18.

PMID: 38200568 PMC: 10782715. DOI: 10.1186/s12957-023-03284-3.

Targeted Mass Spectrometry Reveals Interferon-Dependent Eicosanoid and Fatty Acid Alterations in Chronic Myeloid Leukaemia.

Scott H, Draganov S, Yu Z, Kessler B, Pinto-Fernandez A Int J Mol Sci. 2023; 24(21).

PMID: 37958498 PMC: 10649737. DOI: 10.3390/ijms242115513.

Proteomes of Residual Tumors in Curcumin-Treated Rats Reveal Changes in Microenvironment/Malignant Cell Crosstalk in a Highly Invasive Model of Mesothelioma.

Pouliquen D, Malloci M, Boissard A, Henry C, Guette C Int J Mol Sci. 2022; 23(22).

PMID: 36430209 PMC: 9691155. DOI: 10.3390/ijms232213732.

Regulation of Lipid Metabolism Under Stress and Its Role in Cancer.

Munir R, Zaidi N Subcell Biochem. 2022; 100:81-113.

PMID: 36301492 DOI: 10.1007/978-3-031-07634-3_3.

Chemical inhibition of oxygen-sensing prolyl hydroxylases impairs angiogenic competence of human vascular endothelium through metabolic reprogramming.

Tiwari R, Bommi P, Gao P, Schipma M, Zhou Y, Quaggin S iScience. 2022; 25(10):105086.

PMID: 36157579 PMC: 9494243. DOI: 10.1016/j.isci.2022.105086.

References

Nomura D, Long J, Niessen S, Hoover H, Ng S, Cravatt B . Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010; 140(1):49-61. PMC: 2885975. DOI: 10.1016/j.cell.2009.11.027. View

Buffa F, Harris A, West C, Miller C . Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer. 2010; 102(2):428-35. PMC: 2816644. DOI: 10.1038/sj.bjc.6605450. View

Fletcher J, Haber M, Henderson M, Norris M . ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer. 2010; 10(2):147-56. DOI: 10.1038/nrc2789. View

Semenza G . Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2009; 29(5):625-34. PMC: 2969168. DOI: 10.1038/onc.2009.441. View

Semenza G . HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2009; 20(1):51-6. PMC: 2822127. DOI: 10.1016/j.gde.2009.10.009. View

Guillou H, Zadravec D, Martin P, Jacobsson A . The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice. Prog Lipid Res. 2009; 49(2):186-99. DOI: 10.1016/j.plipres.2009.12.002. View

Vinaixa M, Rodriguez M, Rull A, Beltran R, Blade C, Brezmes J . Metabolomic assessment of the effect of dietary cholesterol in the progressive development of fatty liver disease. J Proteome Res. 2010; 9(5):2527-38. DOI: 10.1021/pr901203w. View

Tun H, Marlow L, von Roemeling C, Cooper S, Kreinest P, Wu K . Pathway signature and cellular differentiation in clear cell renal cell carcinoma. PLoS One. 2010; 5(5):e10696. PMC: 2872663. DOI: 10.1371/journal.pone.0010696. View

Chajes V, Joulin V, Clavel-Chapelon F . The fatty acid desaturation index of blood lipids, as a biomarker of hepatic stearoyl-CoA desaturase expression, is a predictive factor of breast cancer risk. Curr Opin Lipidol. 2010; 22(1):6-10. DOI: 10.1097/MOL.0b013e3283404552. View

10.

Li Y, Xu S, Mihaylova M, Zheng B, Hou X, Jiang B . AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 2011; 13(4):376-388. PMC: 3086578. DOI: 10.1016/j.cmet.2011.03.009. View

11.

Skogerson K, Wohlgemuth G, Barupal D, Fiehn O . The volatile compound BinBase mass spectral database. BMC Bioinformatics. 2011; 12:321. PMC: 3199763. DOI: 10.1186/1471-2105-12-321. View

12.

Wise D, Ward P, Shay J, Cross J, Gruber J, Sachdeva U . Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A. 2011; 108(49):19611-6. PMC: 3241793. DOI: 10.1073/pnas.1117773108. View

13.

Bansal A, Harris R, DeGrado T . Choline phosphorylation and regulation of transcription of choline kinase α in hypoxia. J Lipid Res. 2011; 53(1):149-57. PMC: 3243471. DOI: 10.1194/jlr.M021030. View

14.

Fischer R, Trudgian D, Wright C, Thomas G, Bradbury L, Brown M . Discovery of candidate serum proteomic and metabolomic biomarkers in ankylosing spondylitis. Mol Cell Proteomics. 2011; 11(2):M111.013904. PMC: 3277768. DOI: 10.1074/mcp.M111.013904. View

15.

Melnikova V, Mourad-Zeidan A, Lev D, Bar-Eli M . Platelet-activating factor mediates MMP-2 expression and activation via phosphorylation of cAMP-response element-binding protein and contributes to melanoma metastasis. J Biol Chem. 2005; 281(5):2911-22. DOI: 10.1074/jbc.M508683200. View

16.

Dang D, Chen F, Gardner L, Cummins J, Rago C, Bunz F . Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. Cancer Res. 2006; 66(3):1684-936. DOI: 10.1158/0008-5472.CAN-05-2887. View

17.

Li J, Bosch-Marce M, Nanayakkara A, Savransky V, Fried S, Semenza G . Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1alpha. Physiol Genomics. 2006; 25(3):450-7. DOI: 10.1152/physiolgenomics.00293.2005. View

18.

Balasubramanian L, Evens A . Targeting angiogenesis for the treatment of sarcoma. Curr Opin Oncol. 2006; 18(4):354-9. DOI: 10.1097/01.cco.0000228741.64541.ca. View

19.

Chiang K, Niessen S, Saghatelian A, Cravatt B . An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling. Chem Biol. 2006; 13(10):1041-50. DOI: 10.1016/j.chembiol.2006.08.008. View

20.

Eliyahu G, Kreizman T, Degani H . Phosphocholine as a biomarker of breast cancer: molecular and biochemical studies. Int J Cancer. 2007; 120(8):1721-30. DOI: 10.1002/ijc.22293. View