Skip to main content
SpringerLink
Log in

Modifications in mitochondrial metabolism and ultrastructure and their relationship to tumour growth inhibition by gamma-linolenic acid

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Walker 256 tumour-bearing rats were fed pelleted chow containing low-gamma-linolenic acid (GLA) (2.98%) or high-GLA (5.55%) during the twelve-day period after subcutaneous implantation of the tumour. The presence of n-6, polyunsaturated GLA in the diet caused a concentration-dependent decrease in tumour growth, reaching an almost 50% reduction in final tumour weight in the high-GLA group. The eicosatrienoic acid content of the whole tumour homogenate and of the Percoll-purified mitochondrial fraction was increased by the GLA-rich diets. Changes in the fatty acid composition of the cytoplasmic acyl CoA pool were also found, with increases in GLA content in both the low- and high-GLA groups. Additionally, increases in eicosatrienoic acid and arachidonic acid were found in the high-GLA group. Both the cytoplasmic acyl CoA content and the mitochondrial acyl CoA synthetase activity were increased by GLA in the diet and lipid peroxidation was also increased as determined by an increase in TBARS content. Changes in mitochondrial fatty acid composition were accompanied by a decrease in the mitochondrial membrane potential in the high-GLA group. Tumours from the control and GLA groups were examined by transmission electron microscopy. This revealed an increase in mitochondrial area and volume in the high-GLA group, in comparison with the control group, as well as a change in general cell ultrastructure, with many cells found in an apoptotic state or in a necrotic state, possibly secondary to apoptosis. The data presented show that the addition of GLA to the diet of Walker 256 tumour-bearing rats can greatly decrease the rate of development of the tumour burden. This may be, in part, due to the accumulation of poorly metabolised acyl CoA's within the tumour cell cytoplasm which, when coupled with altered mitochondrial composition, membrane potential and ultrastructure, may be a signal for cell death.

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

Similar content being viewed by others

References

  1. Dagnelie PC, Bell JD, Williams SCR, Bates TE, Abel PD, Foster CS: Effect of fish oil on cancer cachexia and host liver metabolism in rats with prostate tumours. Lipids 29: 195–203, 1994

    Google Scholar 

  2. Cohen LA, Chen-Backlund JY, Sepkovic DW, Sugie S: Effect of varying proportions of dietary menhaden and corn oil on experimental rat mammary tumour promotion. Lipids 28: 449–456, 1993

    Google Scholar 

  3. Wan JMF, Istfan NW, Chu CC, Blackburn GL, Bistrian BR: Comparative effects of ω-3 and ω-6 polyunsaturated fatty acids on protein metabolism in rats bearing the mammary adenocarcinoma. Metabolism 40: 577–584, 1991

    Google Scholar 

  4. Borgeson CE, Pardini L, Pardini RS, Reitz RC: Effects of dietary fish oil on human mammary carcinoma and on lipid-metabolizing enzymes. Lipids 24: 290–295, 1989

    Google Scholar 

  5. Gonzalez MJ, Schemmel RA, Dugan LR, Gray JI, Welsch CW: Dietary fish oil inhibits human breast carcinoma growth: a function of increased lipid peroxidation. Lipids 28: 827–832, 1993

    Google Scholar 

  6. Das UN: Essential fatty acids, lipid peroxidation and apoptosis. Prostagland Leukotrienes Essent Fatty Acids 61: 157–163, 1999

    Google Scholar 

  7. Jump DB, Clarke SD, Thelen A, Liimatta M: Coordinate regulation of glycolytic and lipogenic gene expression by polyunsaturated fatty acids. J Lipid Res 35: 1076–1084, 1994

    Google Scholar 

  8. Jump DB, Clarke SD, Thelen A, Liimatta M, Ren B, Badin M: Dietary polyunsaturated fatty acid regulation of gene transcription. Prog Lipid Res 35: 227–241, 1996

    Google Scholar 

  9. Colquhoun A, de Mello FEP, Curi R: Regulation of tumour cell fatty acid oxidation by n-6 polyunsaturated fatty acids. Biochem Mol Biol Int 44: 143–150, 1998

    Google Scholar 

  10. Colquhoun A: Induction of apoptosis by polyunsaturated fatty acids and its relationship to fatty acid inhibition of carnitine palmitoyltransferase I activity in Hep2 cells. Biochem Mol Biol Int 45: 331–336, 1998

    Google Scholar 

  11. Paumen MB, Ishida Y, Muramatsu M, Yamamoto M, Honjo T: Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem 272: 3324–3329, 1997

    Google Scholar 

  12. Paumen MB, Ishida Y, Han H, Muramatsu M, Eguchi Y, Tsujimoto T, Honjo T: Direct interaction of the mitochondrial membrane protein carnitine palmitoyltransferase I with Bcl-2. BBRes Commun 231: 523-525, 1997

    Google Scholar 

  13. Bégin ME, Ells G, Das UN, Horribin DF: Differentail killing of human carcinoma cell supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 77: 1053–1062, 1986

    Google Scholar 

  14. Bégin ME, Ells G and Horribin DF: Polyunsaturated fatty acid-induced cytotoxicity against tumor cells and its relationship to lipid peroxidation. J Natl Cancer Inst 80: 188–194, 1988

    Google Scholar 

  15. Weber JM, Sircar S, Bégin ME: Greater sensitivity of human multidrugresistant (mdr) cancer cells to polyunsaturated fatty acids than their non-mdr counterparts. J Natl Cancer Inst 86: 38–39, 1994

    Google Scholar 

  16. Jiang WG, Hiscox S, Horrobin DF, Bryce RP, Mansel RE: Gammalinolenic acid regulates expression of maspin and the motility of cancer cells. Biochem Biophys Res Commun 237: 639–644, 1997

    Google Scholar 

  17. Jiang WG, Hiscox S, Hallett MB, Horrobin DF, Mansel RE, Puntis MC: Regulation of the expression of E-cadherin on human cancer cells by gamma-linolenic acid (GLA). Cancer Res 55: 5043–5048, 1995

    Google Scholar 

  18. Jiang WG, Hiscox S, Horrobin DF, Hallett MB, Mansel RE, Puntis MC: Expression of catenins in human cancer cells and its regulation by n-6 polyunsaturated fatty acids. Anticancer Res 15: 2569–2573, 1995

    Google Scholar 

  19. Jiang WG, Singhrao SK, Hiscox S, Hallett MB, Bryce RP, Horrobin DF, Puntis MC, Mansel RE: Regulation of desmosomal cell adhesion in human tumour cells by polyunsaturated fatty acids. Clin Exp Metastasis 15: 593–602, 1997

    Google Scholar 

  20. Davies CL, Loizidou M, Cooper AJ, Taylor I: Effect of gamma-linolenic acid on cellular uptake of structurally related anthracyclines in human drug sensitive and multidrug resistant bladder and breast cancer cell lines. Eur J Cancer 35: 1534–1540, 1999

    Google Scholar 

  21. Fearon KC, Falconer JS, Ross JA, Carter DC, Hunter JO, Reynolds PD, Tuffnell Q: An open-label phase I/II dose escalation study of the treatment of pancreatic cancer using lithium gammalinolenate. Anticancer Res 16: 867–874, 1996

    Google Scholar 

  22. Kairemo KJ, Jekunen AP, Korppi-Tommola ET, Pyrhonen SO: Effects of lithium gammalinolenate on the perfusion of liver and pancreatic tissues in pancreatic cancer. Anticancer Res 17: 3729–3736, 1997

    Google Scholar 

  23. Kenny FS, Pinder SE, Ellis IO, Gee JM, Nicholson RI, Bryce RP, Robertson JF: Gamma-linolenic acid with tamoxifen as primary therapy in breast cancer. Int J Cancer 85: 643–648, 2000

    Google Scholar 

  24. Faergemen NJ, Knudsen J: Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling. Biochem J 323: 1–12, 1997

    Google Scholar 

  25. Colquhoun A, Curi R: Human and rat tumour cells possess mitochondrial carnitine palmitoyltransferase I and II: Effects of insulin. Biochem Mol Biol Int 37: 599–605, 1995

    Google Scholar 

  26. Winterbourn CC, Gutteridge JM, Halliwell B: Doxorubicin dependent lipid peroxidation and peroxidative tissue injury. J Free Rad Biol Med 9: 515–540, 1990

    Google Scholar 

  27. Folch J, Lees M, Sloane-Stanley GH: A simple method for the isolation and purification of total lipids from animal tissue. J Biol Chem 226: 497–509, 1957

    Google Scholar 

  28. Kitson G, Larsen BS, McEwen CN: Gas Chromatography and Mass Spectrometry: A Practical Guide. Academic Press Inc., NY, 1996, p 337

    Google Scholar 

  29. Corkey BE, Brandt M, Williams RJ, Williamson JR: Assay of shortchain acyl coenzyme A intermediates in tissue extracts by high-pressure liquid chromatography. Anal Biochem 118: 30–41, 1981

    Google Scholar 

  30. Ves-Losada A, Brenner RR: Long-chain fatty acyl-CoA synthetase enzymatic activity in rat liver cell nuclei. Mol Cell Biochem 159: 1-6, 1996

    Google Scholar 

  31. Lowry OH, Rosebrough NJ, Farr AL, Randall, RJ: Protein measurement with Folin phenol reagent. J Biol Chem 193: 265–275, 1951

    Google Scholar 

  32. Colquhoun A, de Mello FEP, Curi R: In vivo inhibition of Walker 256 tumour carnitine palmitoyltransferase I by soya oil dietary supplementation. Biochem Mol Biol Int 44: 151–156, 1998

    Google Scholar 

  33. Watkins SM, Carter LC, German JB: Docosahexaenoic acid accumulates in cardiolipin and enhances HT-29 cell oxidant production. J Lipid Res 39: 1583–1588, 1998

    Google Scholar 

  34. Hrelia S, Bordoni A, Biagi P, Rossi CA, Bernardi L, Horrobin DF, Pession A: Gamma-linolenic acid supplementation can affect cancer cell proliferation via modification of fatty acid composition. Biochem Biophys Res Commun 225: 441–447, 1996

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Histologia e Embriologia, Instituto de Ciências Biomédicas, Instituto de Química, Universidade de São Paulo, CEP 05508-900, São Paulo, SP, Brasil

    Alison Colquhoun

  2. Departamento de Bioquímica, Instituto de Ciências Biomédicas, Instituto de Química, Universidade de São Paulo, CEP 05508-900, São Paulo, SP, Brasil

    Robert I. Schumacher

Authors
  1. Alison Colquhoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert I. Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alison Colquhoun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Colquhoun, A., Schumacher, R.I. Modifications in mitochondrial metabolism and ultrastructure and their relationship to tumour growth inhibition by gamma-linolenic acid. Mol Cell Biochem 218, 13–20 (2001). https://doi.org/10.1023/A:1007243922393

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007243922393

Search

Navigation