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Membrane lipid profile alterations are associated with the metabolic adaptation of the Caco-2 cells to aglycemic nutritional condition

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Abstract

Cancer cells can adapt their metabolic activity under nutritional hostile conditions in order to ensure both bioenergetics and biosynthetic requirements to survive. In this study, the effect of glucose deprivation on Caco-2 cells bioenergetics activity and putative relationship with membrane lipid changes were investigated. Glucose deprivation induces a metabolic remodeling characterized at mitochondrial level by an increase of oxygen consumption, arising from an improvement of complex II and complex IV activities and an inhibition of complex I activity. This effect is accompanied by changes in cellular membrane phospholipid profile. Caco-2 cells grown under glucose deprivation show higher phosphatidylethanolamine content and decreased phosphatidic acid content. Considering fatty acid profile of all cell phospholipids, glucose deprivation induces a decrease of monounsaturated fatty acid (MUFA) and n-3 polyunsaturated fatty acids (PUFA) simultaneously with an increase of n-6 PUFA, with consequent drop of n-3/n-6 ratio. Additionally, glucose deprivation affects significantly the fatty acid profile of all individual phospholipid classes, reflected by an increase of peroxidability index in zwitterionic phospholipids and a decrease in all anionic phospholipids, including mitochondrial cardiolipin. These data indicate that Caco-2 cells metabolic remodeling induced by glucose deprivation actively involves membrane lipid changes associated with a specific bioenergetics profile which ensure cell survival.

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References

  • Baritaki S, Apostolakis S, Kanellou P, Dimanche-Boitrel MT, Spandidos DA, Bonavida B (2007) Reversal of tumor resistance to apoptotic stimuli by alteration of membrane fluidity: therapeutic implications. Adv Cancer Res 98:149–190. doi:10.1016/S0065-230X(06)98005-1

    Article  CAS  Google Scholar 

  • Barrientos A, Fontanesi F, Diaz F (2009) Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using polarography and spectrophotometric enzyme assays. Curr Protoc Hum Genet Chapter 19, Unit19 13. doi:10.1002/0471142905.hg1903s63

  • Bartlett GR (1959) Phosphorus assay in column chromatography. J Biol Chem 234(3):466–468

    CAS  Google Scholar 

  • Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37(8):911–917

    Article  CAS  Google Scholar 

  • Campanella R (1992) Membrane lipids modifications in human gliomas of different degree of malignancy. J Neurosurg Sci 36(1):11–25

    CAS  Google Scholar 

  • Canuto RA, Biocca ME, Muzio G, Dianzani MU (1989) Fatty acid composition of phospholipids in mitochondria and microsomes during diethylnitrosamine carcinogenesis in rat liver. Cell Biochem Funct 7(1):11–19. doi:10.1002/cbf.290070104

    Article  CAS  Google Scholar 

  • Chang NW, Wu CT, Chen DR, Yeh CY, Lin C (2013) High levels of arachidonic acid and peroxisome proliferator-activated receptor-alpha in breast cancer tissues are associated with promoting cancer cell proliferation. J Nutr Biochem 24(1):274–281. doi:10.1016/j.jnutbio.2012.06.005

    Article  CAS  Google Scholar 

  • Chicco AJ, Sparagna GC (2007) Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292(1):C33–C44. doi:10.1152/ajpcell.00243.2006

    Article  CAS  Google Scholar 

  • Das UN (2006) Essential fatty acids: biochemistry, physiology and pathology. Biotechnol J 1(4):420–439. doi:10.1002/biot.200600012

    Article  CAS  Google Scholar 

  • DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S et al (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104(49):19345–19350. doi:10.1073/pnas.0709747104

    Article  CAS  Google Scholar 

  • Ellis CE, Murphy EJ, Mitchell DC, Golovko MY, Scaglia F, Barcelo-Coblijn GC et al (2005) Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein. Mol Cell Biol 25(22):10190–10201. doi:10.1128/MCB.25.22.10190-10201.2005

    Article  CAS  Google Scholar 

  • Fields RD, Lancaster MV (1993) Dual-attribute continuous monitoring of cell proliferation/cytotoxicity. Am Biotechnol Lab 11(4):48–50

    CAS  Google Scholar 

  • Filipp FV, Scott DA, Ronai ZA, Osterman AL, Smith JW (2012) Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell Melanoma Res 25(3):375–383. doi:10.1111/j.1755-148X.2012.00989.x, Research Support, N.I.H., Extramural

    Article  CAS  Google Scholar 

  • Freeman MR, Solomon KR (2004) Cholesterol and prostate cancer. J Cell Biochem 91(1):54–69. doi:10.1002/jcb.10724

    Article  CAS  Google Scholar 

  • Frezza C, Cipolat S, Scorrano L (2007) Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts. Nat Protoc 2(2):287–295. doi:10.1038/nprot.2006.478, Research Support, Non-U.S. Gov’t

    Article  CAS  Google Scholar 

  • Funahashi H, Satake M, Hasan S, Sawai H, Newman RA, Reber HA et al (2008) Opposing effects of n-6 and n-3 polyunsaturated fatty acids on pancreatic cancer growth. Pancreas 36(4):353–362. doi:10.1097/MPA.0b013e31815ccc44

    Article  CAS  Google Scholar 

  • Gonzalvez F, Schug ZT, Houtkooper RH, MacKenzie ED, Brooks DG, Wanders RJ et al (2008) Cardiolipin provides an essential activating platform for caspase-8 on mitochondria. J Cell Biol 183(4):681–696. doi:10.1083/jcb.200803129

    Article  CAS  Google Scholar 

  • Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177(2):751–766

    CAS  Google Scholar 

  • Greiner EF, Guppy M, Brand K (1994) Glucose is essential for proliferation and the glycolytic enzyme induction that provokes a transition to glycolytic energy production. J Biol Chem 269(50):31484–31490, In Vitro Research Support, Non-U.S. Gov’t

    CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70, Research Support, U.S. Gov’t, Non-P.H.S.Research Support, U.S. Gov’t, P.H.S.Review

    Article  CAS  Google Scholar 

  • Hauff KD, Hatch GM (2006) Cardiolipin metabolism and Barth Syndrome. Prog Lipid Res 45(2):91–101. doi:10.1016/j.plipres.2005.12.001

    Article  CAS  Google Scholar 

  • Huang TC, Chen CP, Raftery A, Wefler V (1961) A stable reagent for Liebermann-Burchard reaction—application to rapid serum cholesterol determination. Anal Chem 33(10):1405–1407

    Article  CAS  Google Scholar 

  • Jose C, Melser S, Benard G, Rossignol R (2013) Mitoplasticity: adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis. Antioxid Redox Signal 18(7):808–849. doi:10.1089/ars.2011.4357

    Article  CAS  Google Scholar 

  • Jowett M (1931) The phosphatide and cholesterol contents of normal and malignant human tissues. Biochem J 25(6):1991–1998

    CAS  Google Scholar 

  • Kagan VE, Bayir HA, Belikova NA, Kapralov O, Tyurina YY, Tyurin VA et al (2009) Cytochrome c/cardiolipin relations in mitochondria: a kiss of death. Free Radic Biol Med 46(11):1439–1453. doi:10.1016/j.freeradbiomed.2009.03.004

    Article  CAS  Google Scholar 

  • Kanthan R, Senger JL, Kanthan SC (2012) Molecular events in primary and metastatic colorectal carcinoma: a review. Pathol Res Int 2012:597497. doi:10.1155/2012/597497

    Article  Google Scholar 

  • Kolanjiappan K, Ramachandran CR, Manoharan S (2003) Biochemical changes in tumor tissues of oral cancer patients. Clin Biochem 36(1):61–65

    Article  CAS  Google Scholar 

  • Lepage G, Levy E, Ronco N, Smith L, Galeano N, Roy CC (1989) Direct transesterification of plasma fatty acids for the diagnosis of essential fatty acid deficiency in cystic fibrosis. J Lipid Res 30(10):1483–1490

    CAS  Google Scholar 

  • Li YC, Park MJ, Ye SK, Kim CW, Kim YN (2006) Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents. Am J Pathol 168(4):1107–1118. doi:10.2353/ajpath.2006.050959, quiz 1404–1105

    Article  CAS  Google Scholar 

  • Madeira VM, Antunes-Madeira MC, Carvalho AP (1974) Activation energies of the ATPase activity of sarcoplasmic reticulum. Biochem Biophys Res Commun 58(4):897–904

    Article  CAS  Google Scholar 

  • Mashima T, Seimiya H, Tsuruo T (2009) De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer 100(9):1369–1372. doi:10.1038/sj.bjc.6605007, Research Support, Non-U.S. Gov’t Review

    Article  CAS  Google Scholar 

  • Mazurek J, Ignatowicz L, Kallenius G, Svenson SB, Pawlowski A, Hamasur B (2012) Divergent effects of mycobacterial cell wall glycolipids on maturation and function of human monocyte-derived dendritic cells. PLoS One 7(8):e42515. doi:10.1371/journal.pone.0042515

    Article  CAS  Google Scholar 

  • Melo T, Videira RA, Andre S, Maciel E, Francisco CS, Oliveira-Campos AM et al (2012) Tacrine and its analogues impair mitochondrial function and bioenergetics: a lipidomic analysis in rat brain. J Neurochem 120(6):998–1013. doi:10.1111/j.1471-4159.2011.07636.x

    CAS  Google Scholar 

  • Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7(10):763–777. doi:10.1038/nrc2222

    Article  CAS  Google Scholar 

  • Miura N, Matsumoto Y, Miyairi S, Nishiyama S, Naganuma A (1999) Protective effects of triterpene compounds against the cytotoxicity of cadmium in HepG2 cells. Mol Pharmacol 56(6):1324–1328

    CAS  Google Scholar 

  • Munoz-Pinedo C, El Mjiyad N, Ricci JE (2012) Cancer metabolism: current perspectives and future directions. Cell Death Dis 3:e248. doi:10.1038/cddis.2011.123, Research Support, Non-U.S. Gov’tn Review

    Article  CAS  Google Scholar 

  • Murai T (2012) The role of lipid rafts in cancer cell adhesion and migration. Int J Cell Biol 2012:763283. doi:10.1155/2012/763283

    Article  Google Scholar 

  • Pegorier JP, Le May C, Girard J (2004) Control of gene expression by fatty acids. J Nutr 134(9):2444S–2449S, Research Support, Non-U.S. Gov’t Review

    CAS  Google Scholar 

  • Peixoto F, Vicente J, Madeira VM (2004) A comparative study of plant and animal mitochondria exposed to paraquat reveals that hydrogen peroxide is not related to the observed toxicity. Toxicol in Vitro 18(6):733–739. doi:10.1016/j.tiv.2004.02.009

    Article  CAS  Google Scholar 

  • Peskin BS, Carter MJ (2008) Chronic cellular hypoxia as the prime cause of cancer: what is the de-oxygenating role of adulterated and improper ratios of polyunsaturated fatty acids when incorporated into cell membranes? Med Hypotheses 70(2):298–304. doi:10.1016/j.mehy.2007.05.033

    Article  CAS  Google Scholar 

  • Ralph SJ, Rodriguez-Enriquez S, Neuzil J, Moreno-Sanchez R (2010) Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger. Mol Asp Med 31(1):29–59. doi:10.1016/j.mam.2009.12.006

    Article  CAS  Google Scholar 

  • Reitzer LJ, Wice BM, Kennell D (1979) Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 254(8):2669–2676

    CAS  Google Scholar 

  • Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA (2004) Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 64(3):985–993

    Article  CAS  Google Scholar 

  • Schlame M, Rua D, Greenberg ML (2000) The biosynthesis and functional role of cardiolipin. Prog Lipid Res 39(3):257–288

    Article  CAS  Google Scholar 

  • Schug ZT, Gottlieb E (2009) Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim Biophys Acta 1788(10):2022–2031. doi:10.1016/j.bbamem.2009.05.004

    Article  CAS  Google Scholar 

  • Shelton LM, Huysentruyt LC, Seyfried TN (2010) Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model. Int J Cancer 127(10):2478–2485. doi:10.1002/ijc.25431

    Article  CAS  Google Scholar 

  • Shepherd D, Garland PB (1969) The kinetic properties of citrate synthase from rat liver mitochondria. Biochem J 114(3):597–610, In Vitro

    CAS  Google Scholar 

  • Smolkova K, Bellance N, Scandurra F, Genot E, Gnaiger E, Plecita-Hlavata L et al (2010) Mitochondrial bioenergetic adaptations of breast cancer cells to aglycemia and hypoxia. J Bioenerg Biomembr 42(1):55–67. doi:10.1007/s10863-009-9267-x

    Article  CAS  Google Scholar 

  • Stadlmann S, Renner K, Pollheimer J, Moser PL, Zeimet AG, Offner FA et al (2006) Preserved coupling of oxidative phosphorylation but decreased mitochondrial respiratory capacity in IL-1beta-treated human peritoneal mesothelial cells. Cell Biochem Biophys 44(2):179–186. doi:10.1385/CBB:44:2:179

    Article  CAS  Google Scholar 

  • Tawadros T, Brown MD, Hart CA, Clarke NW (2012) Ligand-independent activation of EphA2 by arachidonic acid induces metastasis-like behaviour in prostate cancer cells. Br J Cancer 107(10):1737–1744. doi:10.1038/bjc.2012.457

    Article  CAS  Google Scholar 

  • Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R et al (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18(3):207–219. doi:10.1016/j.ccr.2010.08.009

    Article  CAS  Google Scholar 

  • Warburg O (1956) On respiratory impairment in cancer cells. Science 124(3215):269–270

    CAS  Google Scholar 

  • Weber K, Ridderskamp D, Alfert M, Hoyer S, Wiesner RJ (2002) Cultivation in glucose-deprived medium stimulates mitochondrial biogenesis and oxidative metabolism in HepG2 hepatoma cells. Biol Chem 383(2):283–290. doi:10.1515/BC.2002.030

    Article  CAS  Google Scholar 

  • Weinberg F, Chandel NS (2009) Mitochondrial metabolism and cancer. Ann N Y Acad Sci 1177:66–73. doi:10.1111/j.1749-6632.2009.05039.x

    Article  CAS  Google Scholar 

  • Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M et al (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A 107(19):8788–8793. doi:10.1073/pnas.1003428107

    Article  CAS  Google Scholar 

  • Yamaguchi H, Oikawa T (2010) Membrane lipids in invadopodia and podosomes: key structures for cancer invasion and metastasis. Oncotarget 1(5):320–328, Research Support, Non-U.S. Gov’t Review

    Google Scholar 

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Authors and Affiliations

  1. Chemistry Department, School of Life and Environmental Sciences, University of Trás-os-Montes and Alto Douro (UTAD), P.O. Box 1013, 5001-801, Vila Real, Portugal

    Vera F. Monteiro-Cardoso, Maria M. Oliveira, Francisco Peixoto & Romeu A. Videira

  2. Animal and Veterinary Research Centre (CECAV), UTAD, P.O. Box 1013, 5001-801, Vila Real, Portugal

    Vera F. Monteiro-Cardoso & Romeu A. Videira

  3. Department of Biology and Environment, School of Life and Environmental Sciences, UTAD, P.O. Box 1013, 5001-801, Vila Real, Portugal

    Amélia M. Silva

  4. Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, P.O. Box 1013, 5001-801, Vila Real, Portugal

    Amélia M. Silva & Francisco Peixoto

  5. Chemistry Center – Vila Real (CQ-VR), UTAD, P.O. Box 1013, 5001-801, Vila Real, Portugal

    Maria M. Oliveira

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  1. Vera F. Monteiro-Cardoso
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  2. Amélia M. Silva
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Correspondence to Romeu A. Videira.

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Monteiro-Cardoso, V.F., Silva, A.M., Oliveira, M.M. et al. Membrane lipid profile alterations are associated with the metabolic adaptation of the Caco-2 cells to aglycemic nutritional condition. J Bioenerg Biomembr 46, 45–57 (2014). https://doi.org/10.1007/s10863-013-9531-y

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  • DOI: https://doi.org/10.1007/s10863-013-9531-y

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