Skip to main content

Advertisement

SpringerLink
Log in

Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Cancer cells rewire metabolic processes to adapt to the nutrient- and oxygen-deprived tumour microenvironment, thereby promoting their proliferation and metastasis. Previous research has shown that modifying glucose metabolism, the Warburg effect, makes glycolytic cancer cells more invasive and aggressive. Lipid metabolism has also been receiving attention because lipids function as energy sources and signalling molecules. Because obesity is a risk factor for various cancer types, targeting lipid metabolism may be a promising cancer therapy. Here, we review the lipid metabolic reprogramming in cancer cells mediated by hypoxia-inducible factor-1 (HIF-1). HIF-1 is the master transcription factor for tumour growth and metastasis by transactivating genes related to proliferation, survival, angiogenesis, invasion, and metabolism. The glucose metabolic shift (the Warburg effect) is mediated by HIF-1. Recent research on HIF-1-related lipid metabolic reprogramming in cancer has confirmed that HIF-1 also modifies lipid accumulation, β-oxidation, and lipolysis in cancer, triggering its progression. Therefore, targeting lipid metabolic alterations by HIF-1 has therapeutic potential for cancer. We summarize the role of the lipid metabolic shift mediated by HIF-1 in cancer and its putative applications for cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kory N, Farese RV, Jr., Walther T C. (2016) Targeting fat: mechanisms of protein localization to lipid droplets. Trends Cell Biol 26:535–546. https://doi.org/10.1016/j.tcb.2016.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Murphy DJ (2012) The dynamic roles of intracellular lipid droplets: from archaea to mammals. Protoplasma 249:541–585. https://doi.org/10.1007/s00709-011-0329-7

    Article  CAS  PubMed  Google Scholar 

  3. Thiam AR, Farese RV, Jr., Walther T C. (2013) The biophysics and cell biology of lipid droplets. Nat Rev Mol Cell Biol 14:775–786. https://doi.org/10.1038/nrm3699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Walther TC, Farese RV, Jr. (2012) Lipid droplets and cellular lipid metabolism. Annu Rev Biochem 81:687–714. https://doi.org/10.1146/annurev-biochem-061009-102430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Olzmann JA, Carvalho P (2019) Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol 20:137–155. https://doi.org/10.1038/s41580-018-0085-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. English D (1996) Phosphatidic acid: a lipid messenger involved in intracellular and extracellular signalling. Cell Signal 8:341–347. https://doi.org/10.1016/0898-6568(95)00076-3

    Article  CAS  PubMed  Google Scholar 

  7. Andresen BT, Rizzo MA, Shome K, Romero G (2002) The role of phosphatidic acid in the regulation of the Ras/MEK/Erk signaling cascade. FEBS Lett 531:65–68. https://doi.org/10.1016/S0014-5793(02)03483-X

    Article  CAS  PubMed  Google Scholar 

  8. Jeong DW, Lee SB, Chun YS (2021) How cancer cells remodel lipid metabolism: strategies targeting transcription factors. Lipids Health Dis 20:163. https://doi.org/10.1186/s12944-021-01593-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Papackova Z, Cahova M (2015) Fatty acid signaling: the new function of intracellular lipases. Int J Mol Sci 16:3831–3855. https://doi.org/10.3390/ijms16023831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nadolski MJ, Linder ME (2007) Protein lipidation Febs Journal 274:5202–5210. https://doi.org/10.1111/j.1742-4658.2007.06056.x

    Article  CAS  PubMed  Google Scholar 

  11. Lega IC, Lipscombe LL (2020) Review: diabetes, obesity, and cancer-pathophysiology and clinical implications. Endocr Rev 41:33–52. https://doi.org/10.1210/endrev/bnz014

    Article  Google Scholar 

  12. Seo JE, Kim KS, Park JW, Cho JY, Chang H, Fukuda J, Hong KY, Chun YS (2021) Metastasis-on-a-chip reveals adipocyte-derived lipids trigger cancer cell migration via HIF-1α activation in cancer cells. Biomaterials 269:120622. https://doi.org/10.1016/j.biomaterials.2020.120622

    Article  CAS  PubMed  Google Scholar 

  13. Beloribi-Djefaflia S, Vasseur S, Guillaumond F (2016) Lipid metabolic reprogramming in cancer cells. Oncogenesis 5:e189. https://doi.org/10.1038/oncsis.2015.49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS (2000) Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Can Res 60:4010–4015

    CAS  Google Scholar 

  15. Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454. https://doi.org/10.1128/mcb.12.12.5447-5454.1992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:17771–17778. https://doi.org/10.1074/jbc.271.30.17771

    Article  CAS  PubMed  Google Scholar 

  17. Dengler VL, Galbraith M, Espinosa JM (2014) Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol 49:1–15. https://doi.org/10.3109/10409238.2013.838205

    Article  CAS  PubMed  Google Scholar 

  18. Li H, Ko HP, Whitlock JP (1996) Induction of phosphoglycerate kinase 1 gene expression by hypoxia. Roles of Arnt and HIF1alpha. J Biol Chem 271:21262–21267. https://doi.org/10.1074/jbc.271.35.21262

    Article  CAS  PubMed  Google Scholar 

  19. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472. https://doi.org/10.1126/science.1059796

    Article  CAS  PubMed  Google Scholar 

  20. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427. https://doi.org/10.1038/35017054

    Article  CAS  PubMed  Google Scholar 

  21. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239. https://doi.org/10.1007/s10555-007-9055-1

    Article  CAS  PubMed  Google Scholar 

  22. Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Activation of the HIF pathway in cancer. Curr Opin Genet Dev 11:293–299. https://doi.org/10.1016/s0959-437x(00)00193-3

    Article  CAS  PubMed  Google Scholar 

  23. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 277:29936–29944. https://doi.org/10.1074/jbc.M204733200

    Article  CAS  PubMed  Google Scholar 

  24. Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL (2007) RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol Cell 25:207–217. https://doi.org/10.1016/j.molcel.2007.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Richard DE, Berra E, Pouyssegur J (2000) Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem 275:26765–26771. https://doi.org/10.1074/jbc.M003325200

    Article  CAS  PubMed  Google Scholar 

  26. Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B (1998) Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J 17:5085–5094. https://doi.org/10.1093/emboj/17.17.5085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL (2000) Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60:1541–1545

    CAS  PubMed  Google Scholar 

  28. Haase VH (2013) Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev 27:41–53. https://doi.org/10.1016/j.blre.2012.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lu X, Kang Y (2010) Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 16:5928–5935. https://doi.org/10.1158/1078-0432.CCR-10-1360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Welker MW, Trojan J (2013) Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety. Cancer Manag Res 5:337–347. https://doi.org/10.2147/CMAR.S35029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10:295–305. https://doi.org/10.1038/ncb1691

    Article  CAS  PubMed  Google Scholar 

  32. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713. https://doi.org/10.1038/nrc2468

    Article  CAS  PubMed  Google Scholar 

  33. Harris AL (2002) Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47. https://doi.org/10.1038/nrc704

    Article  CAS  PubMed  Google Scholar 

  34. Kress S, Stein A, Maurer P, Weber B, Reichert J, Buchmann A, Huppert P, Schwarz M (1998) Expression of hypoxia-inducible genes in tumor cells. J Cancer Res Clin Oncol 124:315–320. https://doi.org/10.1007/s004320050175

    Article  CAS  PubMed  Google Scholar 

  35. Rodriguez H, Drouin R, Holmquist GP, Akman SA (1997) A hot spot for hydrogen peroxide-induced damage in the human hypoxia-inducible factor 1 binding site of the PGK 1 gene. Arch Biochem Biophys 338:207–212. https://doi.org/10.1006/abbi.1996.9820

    Article  CAS  PubMed  Google Scholar 

  36. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732. https://doi.org/10.1038/nrc1187

    Article  CAS  PubMed  Google Scholar 

  37. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20:51–56. https://doi.org/10.1016/j.gde.2009.10.009

    Article  CAS  PubMed  Google Scholar 

  38. Dang CV, Semenza GL (1999) Oncogenic alterations of metabolism. Trends Biochem Sci 24:68–72. https://doi.org/10.1016/s0968-0004(98)01344-9

    Article  CAS  PubMed  Google Scholar 

  39. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang HM, Cinalli RM, Alavi A, Rudin CM, Thompson CB (2004) Akt stimulates aerobic glycolysis in cancer cells. Can Res 64:3892–3899. https://doi.org/10.1158/0008-5472.CAN-03-2904

    Article  CAS  Google Scholar 

  40. Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41:211–218. https://doi.org/10.1016/j.tibs.2015.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kim J-w, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185. https://doi.org/10.1016/j.cmet.2006.02.002

    Article  CAS  PubMed  Google Scholar 

  42. Holleran AL, Briscoe DA, Fiskum G, Kelleher JK (1995) Glutamine metabolism in AS-30D hepatoma cells. Evidence for its conversion into lipids via reductive carboxylation. Mol Cell Biochem 152:95–101. https://doi.org/10.1007/BF01076071

    Article  CAS  PubMed  Google Scholar 

  43. Daye D, Wellen KE (2012) Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol 23:362–369. https://doi.org/10.1016/j.semcdb.2012.02.002

    Article  CAS  PubMed  Google Scholar 

  44. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang JJ, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G (2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:380–384. https://doi.org/10.1038/nature10602

    Article  CAS  Google Scholar 

  45. Wise DR, P.S. Ward P S, Shay J E, Cross J R, Gruber J J, Sachdeva U M, Platt J M, DeMatteo R G, Simon M C, Thompson C B. (2011) Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. PNAS 108:19611–19616. https://doi.org/10.1073/pnas.1117773108

    Article  PubMed  PubMed Central  Google Scholar 

  46. Gameiro PA, Yang JJ, Metelo AM, Perez-Carro R, Baker R, Wang ZW, Arreola A, Rathmell WK, Olumi A, Lopez-Larrubia P, Stephanopoulos G, Iliopoulos O (2013) In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab 17:372–385. https://doi.org/10.1016/j.cmet.2013.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sun RC, Denko NC (2014) Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19:285–292. https://doi.org/10.1016/j.cmet.2013.11.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yoo HC, Yu YC, Sung Y, Han JM (2020) Glutamine reliance in cell metabolism. Exp Mol Med 52:1496–1516. https://doi.org/10.1038/s12276-020-00504-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Qiu JF, Zhang KL, Zhang XJ, Hu YJ, Li P, Shang CZ, Wan JB (2015) Abnormalities in plasma phospholipid fatty acid profiles of patients with hepatocellular carcinoma. Lipids 50:977–985. https://doi.org/10.1007/s11745-015-4060-6

    Article  CAS  PubMed  Google Scholar 

  50. Mika A, Kobiela J, Czumaj A, Chmielewski M, Stepnowski P, Sledzinski T (2017) Hyper-elongation in colorectal cancer tissue - cerotic acid is a potential novel serum metabolic marker of colorectal malignancies. Cell Physiol Biochem 41:722–730. https://doi.org/10.1159/000458431

    Article  CAS  PubMed  Google Scholar 

  51. Li F, Qin XZ, Chen HQ, Qiu L, Guo YM, Liu H, Chen GQ, Song GG, Wang XD, Li FJ, Guo S, Wang BH, Li ZL (2013) Lipid profiling for early diagnosis and progression of colorectal cancer using direct-infusion electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. Rapid Commun Mass Sp 27:24–34. https://doi.org/10.1002/rcm.6420

    Article  CAS  Google Scholar 

  52. Qiu YP, Cai GX, Zhou BS, Li D, Zhao AH, Xie GX, Li HK, Cai SJ, Xie D, Huang CZ, Ge WT, Zhou ZX, Xu LX, Jia WP, Zheng S, Yen Y, Jia W (2014) A distinct metabolic signature of human colorectal cancer with prognostic potential. Clin Cancer Res 20:2136–2146. https://doi.org/10.1158/1078-0432.CCR-13-1939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pakiet A, Kobiela J, Stepnowski P, Sledzinski T, Mika A (2019) Changes in lipids composition and metabolism in colorectal cancer: a review. Lipids Health Dis 18:29. https://doi.org/10.1186/s12944-019-0977-8

    Article  PubMed  PubMed Central  Google Scholar 

  54. Zhang JJ, Zhang LJ, Ye XX, Chen LY, Zhang LT, Gao YH, Kang JX, Cai C (2013) Characteristics of fatty acid distribution is associated with colorectal cancer prognosis. Prostag Leukotr Ess 88:355–360. https://doi.org/10.1016/j.plefa.2013.02.005

    Article  CAS  Google Scholar 

  55. Baenke F, Peck B, Miess H, Schulze A (2013) Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Dis Model Mech 6:1353–1363. https://doi.org/10.1242/dmm.011338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Solinas G, Boren J, Dulloo AG (2015) De novo lipogenesis in metabolic homeostasis: more friend than foe? Mol Metab 4:367–377. https://doi.org/10.1016/j.molmet.2015.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kusakabe T, Maeda M, Hoshi N, Sugino T, Watanabe K, Fukuda T, Suzuki T (2000) Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells. J Histochem Cytochem 48:613–622. https://doi.org/10.1177/002215540004800505

    Article  CAS  PubMed  Google Scholar 

  58. Wagle S, Bui A, Ballard PL, Shuman H, Gonzales J, Gonzales LW (1999) Hormonal regulation and cellular localization of fatty acid synthase in human fetal lung. Am J Physiol-Lung C 277:L381–L390. https://doi.org/10.1152/ajplung.1999.277.2.L381

    Article  CAS  Google Scholar 

  59. Hatzivassiliou G, Zhao FP, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8:311–321. https://doi.org/10.1016/j.ccr.2005.09.008

    Article  CAS  PubMed  Google Scholar 

  60. Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, Ushijima M, Mashima T, Seimiya H, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y (2008) ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Can Res 68:8547–8554. https://doi.org/10.1158/0008-5472.CAN-08-1235

    Article  CAS  Google Scholar 

  61. Wang Y, Wang YX, Shen L, Pang YX, Qiao Z, Liu PS (2012) Prognostic and therapeutic implications of increased ATP citrate lyase expression in human epithelial ovarian cancer. Oncol Rep 27:1156–1162. https://doi.org/10.3892/or.2012.1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN, Lombardo PS, Van Nostrand JL, Hutchins A, Vera L, Gerken L, Greenwood J, Bhat S, Harriman G, Westlin WF, Harwood HJ, Saghatelian A, Kapeller R, Metallo CM, Shaw RJ (2016) Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 22:1108–1119. https://doi.org/10.1038/nm.4181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ogino S, Nosho K, Meyerhardt JA, Kirkner GJ, Chan AT, Kawasaki T, Giovannucci EL, Loda M, Fuchs CS (2008) Cohort study of fatty acid synthase expression and patient survival in colon cancer. J Clin Oncol 26:5713–5720. https://doi.org/10.1200/JCO.2008.18.2675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shurbaji MS, Kalbfleisch JH, Thurmond TS (1996) Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer. Hum Pathol 27:917–921. https://doi.org/10.1016/s0046-8177(96)90218-x

    Article  CAS  PubMed  Google Scholar 

  65. Takahiro T, Shinichi K, Toshimitsu S (2003) Expression of fatty acid synthase as a prognostic indicator in soft tissue sarcomas. Clin Cancer Res 9:2204–2212

    CAS  PubMed  Google Scholar 

  66. Visca P, Sebastiani V, Botti C, Diodoro MG, Lasagni RP, Romagnoli F, Brenna A, De Joannon BC, Donnorso RP, Lombardi G, Alo PL (2004) Fatty acid synthase (FAS) is a marker of increased risk of recurrence in lung carcinoma. Anticancer Res 24:4169–4173

    CAS  PubMed  Google Scholar 

  67. Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K (2008) Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 68:1003–1011. https://doi.org/10.1158/0008-5472.CAN-07-2489

    Article  CAS  PubMed  Google Scholar 

  68. Lewis CA, Brault C, Peck B, Bensaad K, Griffiths B, Mitter R, Chakravarty P, East P, Dankworth B, Alibhai D, Harris AL, Schulze A (2015) SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme. Oncogene 34:5128–5140. https://doi.org/10.1038/onc.2014.439

    Article  CAS  PubMed  Google Scholar 

  69. Peciuliene I, Vilys L, Jakubauskiene E, Zaliauskiene L, Kanopka A (2019) Hypoxia alters splicing of the cancer associated Fas gene. Exp Cell Res 380:29–35. https://doi.org/10.1016/j.yexcr.2019.04.015

    Article  CAS  PubMed  Google Scholar 

  70. Jung SY, Jeon HK, Choi JS, Kim YJ (2012) Reduced expression of FASN through SREBP-1 down-regulation is responsible for hypoxic cell death in HepG2 cells. J Cell Biochem 113:3730–3739. https://doi.org/10.1002/jcb.24247

    Article  CAS  PubMed  Google Scholar 

  71. Balaban S, Shearer RF, Lee LS, van Geldermalsen M, Schreuder M, Shtein HC, Cairns R, Thomas KC, Fazakerley DJ, Grewal T, Holst J, Saunders DN, Hoy AJ (2017) Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metab 5:1. https://doi.org/10.1186/s40170-016-0163-7

    Article  PubMed  PubMed Central  Google Scholar 

  72. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, Yamada SD, Peter ME, Gwin K, Lengyel E (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17:1498–1503. https://doi.org/10.1038/nm.2492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Su X, Abumrad NA (2009) Cellular fatty acid uptake: a pathway under construction. Trends Endocrin Met 20:72–77. https://doi.org/10.1016/j.tem.2008.11.001

    Article  CAS  Google Scholar 

  74. Calvo D, Gomez-Coronado D, Suarez Y, Lasuncion MA, Vega MA (1998) Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. J Lipid Res 39:777–788. https://doi.org/10.1016/S0022-2275(20)32566-9

    Article  CAS  PubMed  Google Scholar 

  75. Enciu AM, Radu E, Popescu ID, Hinescu ME, Ceafalan LC (2018) Targeting CD36 as biomarker for metastasis prognostic: how far from translation into clinical practice? Biomed Res Int 2018:7801202. https://doi.org/10.1155/2018/7801202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. McKillop LH, Girardi CA, Thompson KJ (2019) Role of fatty acid binding proteins (FABPs) in cancer development and progression. Cell Signal 62:109336. https://doi.org/10.1016/j.cellsig.2019.06.001

    Article  CAS  PubMed  Google Scholar 

  77. Bensaad K, Favaro E, Lewis CA, Peck B, Lord S, Collins JM, Pinnick KE, Wigfield S, Buffa FM, Li JL, Zhang Q, Wakelam MJO, Karpe F, Schulze A, Harris AL (2014) Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep 9:349–365. https://doi.org/10.1016/j.celrep.2014.08.056

    Article  CAS  PubMed  Google Scholar 

  78. Gharpure KM, Pradeep S, Sans M, Rupaimoole R, Ivan C, Wu SY, Bayraktar E, Nagaraja AS, Mangala LS, Zhang XN, Haemmerle M, Hu W, Rodriguez-Aguayo C, McGuire M, Mak CSL, Chen XH, Tran MA, Villar-Prados A, Pena GA, Kondetimmanahalli R, Nini R, Koppula P, Ram P, Liu JS, Lopez-Berestein G, Baggerly K, Eberlin LS, Sood AK (2018) FABP4 as a key determinant of metastatic potential of ovarian cancer. Nat Commun 9:2923. https://doi.org/10.1038/s41467-018-04987-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Seo J, Jeong D-W, Park J-W, Lee K-W, Fukuda J, Chun Y-S (2020) Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells. Communications Biology 3:638. https://doi.org/10.1038/s42003-020-01367-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Seo JE, Yun JE, Fukuda J, Chun YS (2021) Tumor-intrinsic FABP5 is a novel driver for colon cancer cell growth via the HIF-1 signaling pathway. Cancer Genet 258:151–156. https://doi.org/10.1016/j.cancergen.2021.11.001

    Article  CAS  PubMed  Google Scholar 

  81. Khor VK, Shen WJ, Kraemer FB (2013) Lipid droplet metabolism. Curr Opin Clin Nutr 16:632–637. https://doi.org/10.1097/MCO.0b013e3283651106

    Article  CAS  Google Scholar 

  82. Cabodevilla AG, Sanchez-Caballero L, Nintou E, Boiadjieva VG, Picatoste F, Gubern A, Claro E (2013) Cell survival during complete nutrient deprivation depends on lipid droplet-fueled beta-oxidation of fatty acids. J Biol Chem 288:27777–27788. https://doi.org/10.1074/jbc.M113.466656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cotte AK, Aires V, Fredon M, Limagne E, Derangere V, Thibaudin M, Humblin E, Scagliarini A, de Barros JP, Hillon P, Ghiringhelli F, Delmas D (2018) Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance. Nat Commun 9:322. https://doi.org/10.1038/s41467-017-02732-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jarc E, Kump A, Malavasic P, Eichmann TO, Zimmermann R, Petan T (2018) Lipid droplets induced by secreted phospholipase A2 and unsaturated fatty acids protect breast cancer cells from nutrient and lipotoxic stress. Biochim Biophys Acta Mol Cell Biol Lipids 1863:247–265. https://doi.org/10.1016/j.bbalip.2017.12.006

    Article  CAS  PubMed  Google Scholar 

  85. Pucer A, Brglez V, Payre C, Pungercar J, Lambeau G, Petan T (2013) Group X secreted phospholipase A(2) induces lipid droplet formation and prolongs breast cancer cell survival. Mol Cancer 12:111. https://doi.org/10.1186/1476-4598-12-111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Accioly MT, Pacheco P, Maya-Monteiro CM, Carrossini N, Robbs BK, Oliveira SS, Kaufmann C, Morgado-Diaz JA, Bozza PT, Viola JP (2008) Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Res 68:1732–1740. https://doi.org/10.1158/0008-5472.CAN-07-1999

    Article  CAS  PubMed  Google Scholar 

  87. Geng F, Cheng X, Wu X, Yoo JY, Cheng C, Guo JY (2017) Correction: inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis. Clin Cancer Res 23:2127. https://doi.org/10.1158/1078-0432.CCR-17-0063

    Article  Google Scholar 

  88. Sebastiano MR, Konstantinidou G (2019) Targeting long chain Acyl-CoA synthetases for cancer therapy. Int J Mol Sci 20:3624. https://doi.org/10.3390/ijms20153624

    Article  CAS  Google Scholar 

  89. Soupene E, Kuypers FA (2008) Mammalian long-chain Acyl-CoA synthetases. Exp Biol Med 233:507–521. https://doi.org/10.3181/0710-MR-287

    Article  CAS  Google Scholar 

  90. Saponaro C, Gaggini M, Carli F, Gastaldelli A (2015) The subtle balance between lipolysis and lipogenesis: a critical point in metabolic homeostasis. Nutrients 7:9453–9474. https://doi.org/10.3390/nu7115475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mylonis I, Sembongi H, Befani C, Liakos P, Siniossoglou S, Simos G (2012) Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression. J Cell Sci 125:3485–3493. https://doi.org/10.1242/jcs.106682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Triantafyllou EA, Georgatsou E, Mylonis I, Simos G, Paraskeva E (2018) Expression of AGPAT2, an enzyme involved in the glycerophospholipid/triacylglycerol biosynthesis pathway, is directly regulated by HIF-1 and promotes survival and etoposide resistance of cancer cells under hypoxia. Biochim Biophys Acta Mol Cell Biol Lipids 1863:1142–1152. https://doi.org/10.1016/j.bbalip.2018.06.015

    Article  CAS  PubMed  Google Scholar 

  93. Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD, Grazioli A, Bobrovnikova-Marjon E, Diehl JA, Keith B, Simon MC (2015) HIF2 alpha-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov 5:652–667. https://doi.org/10.1158/2159-8290.CD-14-1507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS (2007) Regulation of lipolysis in adipocytes. Annu Rev Nutr 27:79–101. https://doi.org/10.1146/annurev.nutr.27.061406.093734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Carracedo A, Cantley LC, Pandolfi PP (2013) Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13:227–232. https://doi.org/10.1038/nrc3483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Houten SM, Violante S, Ventura FV, Wanders RJA (2016) The biochemistry and physiology of mitochondrial fatty acid beta-oxidation and its genetic disorders. Annu Rev Physiol 78:23–44. https://doi.org/10.1146/annurev-physiol-021115-105045

    Article  CAS  PubMed  Google Scholar 

  97. Zhang XD, Saarinen AM, Hitosugi T, Wang ZH, Wang LG, Ho TH, Liu J (2017) Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia. Elife 6:e31132. https://doi.org/10.7554/eLife.31132

    Article  PubMed  PubMed Central  Google Scholar 

  98. Liu Y, Ma Z, Zhao C, Wang Y, Wu G, Xiao J, McClain CJ, Li X, Feng W (2014) HIF-1alpha and HIF-2alpha are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1alpha-mediated fatty acid beta-oxidation. Toxicol Lett 226:117–123. https://doi.org/10.1016/j.toxlet.2014.01.033

    Article  CAS  PubMed  Google Scholar 

  99. Du W, Zhang L, Brett-Morris A, Aguila B, Kerner J, Hoppel CL, Puchowicz M, Serra D, Herrero L, Rini BI, Campbell S, Welford SM (2017) HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun 8:1769. https://doi.org/10.1038/s41467-017-01965-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Huang D, Li T, Li X, Zhang L, Sun L, He X, Zhong X, Jia D, Song L, Semenza GL, Gao P, Zhang H (2014) HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 8:1930–1942. https://doi.org/10.1016/j.celrep.2014.08.028

    Article  CAS  PubMed  Google Scholar 

  101. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8:224–236. https://doi.org/10.1016/j.cmet.2008.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Luyimbazi D, Akcakanat A, McAuliffe PF, Zhang L, Singh G, Gonzalez-Angulo AM, Chen HQ, Do KA, Zheng YH, Hung MC, Mills GB, Meric-Bernstam F (2010) Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. Mol Cancer Ther 9:2770–2784. https://doi.org/10.1158/1535-7163.MCT-09-0980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Magaway C, Kim E, Jacinto E (2019) Targeting mTOR and metabolism in cancer: lessons and innovations. Cells 8:1584. https://doi.org/10.3390/cells8121584

    Article  CAS  PubMed Central  Google Scholar 

  104. De Souza C, Chatterji BP (2015) HDAC inhibitors as novel anti-cancer therapeutics. Recent Pat Anticancer Drug Discov 10:145–162. https://doi.org/10.2174/1574892810666150317144511

    Article  CAS  PubMed  Google Scholar 

  105. Nunn A, Scopigno T, Pediconi N, Levrero M, Hagman H, Kiskis J, Enejder A (2016) The histone deacetylase inhibiting drug entinostat induces lipid accumulation in differentiated HepaRG cells. Sci Rep 6:28025. https://doi.org/10.1038/srep28025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Brockmueller A, Sameri S, Liskova A, Zhai KV, Varghese E, Samuel SM, Busselberg D, Kubatka P, Shakibaei M (2021) Resveratrol’s anti-cancer effects through the modulation of tumor glucose metabolism. Cancers 13:188. https://doi.org/10.3390/cancers13020188

    Article  CAS  PubMed Central  Google Scholar 

  107. Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP (2011) Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Tar 11:239–253. https://doi.org/10.2174/156800911794519752

    Article  CAS  Google Scholar 

  108. Fonseca J, Moradi F, Maddalena LA, Ferreira-Tollstadius B, Selim S, Stuart JA (2019) Resveratrol integrates metabolic and growth effects in PC3 prostate cancer cells-involvement of prolyl hydroxylase and hypoxia inducible factor-1. Oncol Lett 17:697–705. https://doi.org/10.3892/ol.2018.9526

    Article  CAS  PubMed  Google Scholar 

  109. Haynes J, McKee TD, Haller A, Wang YD, Leung C, Gendoo DMA, Lima-Fernandes E, Kreso A, Wolman R, Szentgyorgyi E, Vines DC, Haibe-Kains B, Wouters BG, Metser U, Jaffray DA, Smith M, O’Brien CA (2018) Administration of hypoxia-activated prodrug evofosfamide after conventional adjuvant therapy enhances therapeutic outcome and targets cancer-initiating cells in preclinical models of colorectal cancer. Clin Cancer Res 24:2116–2127. https://doi.org/10.1158/1078-0432.CCR-17-1715

    Article  CAS  PubMed  Google Scholar 

  110. Huang Y, Tian Y, Zhao YY, Xue C, Zhan JH, Liu L, He XB, Zhang L (2018) Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo. Cancer Commun (Lond) 38:15. https://doi.org/10.1186/s40880-018-0285-0

    Article  Google Scholar 

  111. Li XR, Lu J, Kan QC, Li XL, Fan Q, Li YQ, Huang RX, Slipicevic A, Dong HP, Eide L, Wang JB, Zhang HQ, Berge V, Goscinski MA, Kvalheim G, Nesland JM, Suo ZH (2017) Metabolic reprogramming is associated with flavopiridol resistance in prostate cancer DU145 cells. Sci Rep 7:5081. https://doi.org/10.1038/s41598-017-05086-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Minet E, Mottet D, Michel G, Roland I, Raes M, Remacle J, Michiels C (1999) Hypoxia-induced activation of HIF-1, role of HIF-1 alpha-Hsp90 interaction. Febs Lett 460:251–256. https://doi.org/10.1016/s0014-5793(99)01359-9

    Article  CAS  PubMed  Google Scholar 

  113. Newcomb EW, Ali MA, Schnee T, Lan L, Lukyanov Y, Fowkes M, Miller DC, Zagzag D (2005) Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1 alpha expression in human glioma cells by a proteasome-independent pathway: implications for in vivo therapy. Neuro Oncol 7:225–235. https://doi.org/10.1215/S1152851704000997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Park SY, Jeong KJ, Lee J, Yoon DS, Choi WS, Kim YK, Han JW, Kim YM, Kim BK, Lee HY (2007) Hypoxia enhances LPA-induced HIF-1 alpha and VEGF expression: their inhibition by resveratrol. Cancer Lett 258:63–69. https://doi.org/10.1016/j.canlet.2007.08.011

    Article  CAS  PubMed  Google Scholar 

  115. Scheibel T, Buchner J (1998) The Hsp90 complex - a super-chaperone machine as a novel drug target. Biochem Pharmacol 56:675–682. https://doi.org/10.1016/s0006-2952(98)00120-8

    Article  CAS  PubMed  Google Scholar 

  116. Sedlacek HH (2001) Mechanisms of action of flavopiridol. Crit Rev Oncol Hemat 38:139–170. https://doi.org/10.1016/s1040-8428(00)00124-4

    Article  CAS  Google Scholar 

  117. Shin DH, Chun YS, Lee DS, Huang LE, Park JW (2008) Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1. Blood 111:3131–3136. https://doi.org/10.1182/blood-2007-11-120576

    Article  CAS  PubMed  Google Scholar 

  118. Volmer AA, Szpilman AM, Carreira EM (2010) Synthesis and biological evaluation of amphotericin B derivatives. Nat Prod Rep 27:1329–1349. https://doi.org/10.1039/b820743g

    Article  CAS  PubMed  Google Scholar 

  119. Yeo EJ, Ryu JH, Cho YS, Chun YS, Huang LE, Kim MS, Park JW (2006) Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1. Blood 107:916–923. https://doi.org/10.1182/blood-2005-06-2564

    Article  CAS  PubMed  Google Scholar 

  120. Zhang QZ, Tang XD, Lu QY, Zhang ZF, Brown J, Le AD (2005) Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1 alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells. Mol Cancer Ther 4:1465–1474. https://doi.org/10.1158/1535-7163.MCT-05-0198

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from National Research Foundation of Korea (2018R1A5A2025964 and 2019R1A2C2083886). JS and JEY received a scholarship from the BK21-plus program, Republic of Korea.

Author information

Author notes

    Authors and Affiliations

    1. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea

      Jieun Seo, Jeong-Eun Yun, Sung Joon Kim & Yang-Sook Chun

    2. Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea

      Jieun Seo, Jeong-Eun Yun, Sung Joon Kim & Yang-Sook Chun

    3. Faculty of Engineering, Yokohama National University, Yokohama, 240-8501, Japan

      Jieun Seo

    4. Kanagawa Institute of Industrial Science and Technology, Kawasaki, 213-0012, Japan

      Jieun Seo

    5. Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea

      Sung Joon Kim & Yang-Sook Chun

    Authors
    1. Jieun Seo
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jeong-Eun Yun
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Sung Joon Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yang-Sook Chun
      View author publications

      You can also search for this author in PubMed Google Scholar

    Contributions

    Conceptualization: JS, JEY, and YSC. Validation: JS and JEY. Investigation: JS and JEY. Resources: SJK and YSC. Writing—original draft preparation: JS and JEY. Writing—review and editing: YSC. Visualization: JS and JEY. Supervision: YSC. Project administration: YSC. Funding acquisition: SJK and YSC. All authors have read and agreed to the published version of the manuscript.

    Corresponding author

    Correspondence to Yang-Sook Chun.

    Ethics declarations

    Conflict of interest

    The authors declare no competing interests.

    Additional information

    Publisher's Note

    Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

    These authors contributed equally: Jieun Seo and Jeong-Eun Yun.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Seo, J., Yun, JE., Kim, S.J. et al. Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment. Pflugers Arch - Eur J Physiol 474, 591–601 (2022). https://doi.org/10.1007/s00424-022-02683-x

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00424-022-02683-x

    Keywords

    Search

    Navigation