Abstract
For the past 70 years the dominant perception of cancer metabolism has been that it is fuelled mainly by glucose (via aerobic glycolysis) and glutamine. Consequently, investigations into the diagnosis, treatment and the basic metabolism of cancer cells have been directed by this perception. However, the data on cancer metabolism are equivocal, and in this study we have sought to clarify the issue. Using an innovative system we have measured the total ATP turnover of the MCF-7 breast cancer cell line, the contributions to this turnover by oxidative and glycolytic ATP production and the contributions to the oxidative component by glucose, lactate, glutamine, palmitate and oleate. The total ATP turnover over approx. 5 days was 26.8 micromol of ATP.10(7) cells(-1).h(-1). ATP production was 80% oxidative and 20% glycolytic. Contributions to the oxidative component were approx. 10% glucose, 14% glutamine, 7% palmitate, 4% oleate and 65% from unidentified sources. The contribution by glucose (glycolysis and oxidation) to total ATP turnover was 28.8%, glutamine contributed 10.7% and glucose and glutamine combined contributed 40%. Glucose and glutamine are significant fuels, but they account for less than half of the total ATP turnover. The contribution of aerobic glycolysis is not different from that in a variety of other non-transformed cell types.
Full Text
The Full Text of this article is available as a PDF (123.4 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abas L., Bogoyevitch M. A., Guppy M. Mitochondrial ATP production is necessary for activation of the extracellular-signal-regulated kinases during ischaemia/reperfusion in rat myocyte-derived H9c2 cells. Biochem J. 2000 Jul 1;349(Pt 1):119–126. doi: 10.1042/0264-6021:3490119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aloj L., Caracó C., Jagoda E., Eckelman W. C., Neumann R. D. Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells in culture. Cancer Res. 1999 Sep 15;59(18):4709–4714. [PubMed] [Google Scholar]
- Berry M. N., Phillips J. W., Gregory R. B., Grivell A. R., Wallace P. G. Operation and energy dependence of the reducing-equivalent shuttles during lactate metabolism by isolated hepatocytes. Biochim Biophys Acta. 1992 Sep 9;1136(3):223–230. doi: 10.1016/0167-4889(92)90110-w. [DOI] [PubMed] [Google Scholar]
- Brown J. M. The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res. 1999 Dec 1;59(23):5863–5870. [PubMed] [Google Scholar]
- Busfield S. J., Meyer G. T., Klinken S. P. Erythropoietin induced ultrastructural alterations to J2E cells and loss of proliferative capacity with terminal differentiation. Growth Factors. 1993;9(4):317–328. doi: 10.3109/08977199308991592. [DOI] [PubMed] [Google Scholar]
- Bustamante E., Pedersen P. L. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3735–3739. doi: 10.1073/pnas.74.9.3735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chang S., Lee S., Lee C., Kim J. I., Kim Y. Expression of the human erythrocyte glucose transporter in transitional cell carcinoma of the bladder. Urology. 2000 Mar;55(3):448–452. doi: 10.1016/s0090-4295(99)00474-4. [DOI] [PubMed] [Google Scholar]
- Chung J. K., Lee Y. J., Kim C., Choi S. R., Kim M., Lee K., Jeong J. M., Lee D. S., Jang J. J., Lee M. C. Mechanisms related to [18F]fluorodeoxyglucose uptake of human colon cancers transplanted in nude mice. J Nucl Med. 1999 Feb;40(2):339–346. [PubMed] [Google Scholar]
- Fanciulli M., Valentini A., Bruno T., Citro G., Zupi G., Floridi A. Effect of the antitumor drug lonidamine on glucose metabolism of adriamycin-sensitive and -resistant human breast cancer cells. Oncol Res. 1996;8(3):111–120. [PubMed] [Google Scholar]
- Guppy M., Abas L., Neylon C., Whisson M. E., Whitham S., Pethick D. W., Niu X. Fuel choices by human platelets in human plasma. Eur J Biochem. 1997 Feb 15;244(1):161–167. doi: 10.1111/j.1432-1033.1997.00161.x. [DOI] [PubMed] [Google Scholar]
- Guppy M., Greiner E., Brand K. The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes. Eur J Biochem. 1993 Feb 15;212(1):95–99. doi: 10.1111/j.1432-1033.1993.tb17637.x. [DOI] [PubMed] [Google Scholar]
- Guppy M., Hill D. J., Arthur P., Rowley A. F. Differences in fuel utilization between trout and human thrombocytes in physiological media. J Comp Physiol B. 1999 Oct;169(7):515–520. doi: 10.1007/s003600050250. [DOI] [PubMed] [Google Scholar]
- Guppy M., Kong S. E., Niu X., Busfield S., Klinken S. P. Method for measuring a comprehensive energy budget in a proliferating cell system over multiple cell cycles. J Cell Physiol. 1997 Jan;170(1):1–7. doi: 10.1002/(SICI)1097-4652(199701)170:1<1::AID-JCP1>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
- Guppy M., Whisson M. E., Sabaratnam R., Withers P., Brand K. Alternative fuels for platelet storage: a metabolic study. Vox Sang. 1990;59(3):146–152. doi: 10.1111/j.1423-0410.1990.tb00849.x. [DOI] [PubMed] [Google Scholar]
- Guse A. H., Greiner E., Emmrich F., Brand K. Mass changes of inositol 1,3,4,5,6-pentakisphosphate and inositol hexakisphosphate during cell cycle progression in rat thymocytes. J Biol Chem. 1993 Apr 5;268(10):7129–7133. [PubMed] [Google Scholar]
- Hansen P. A., Marshall B. A., Chen M., Holloszy J. O., Mueckler M. Transgenic overexpression of hexokinase II in skeletal muscle does not increase glucose disposal in wild-type or Glut1-overexpressing mice. J Biol Chem. 2000 Jul 21;275(29):22381–22386. doi: 10.1074/jbc.M001946200. [DOI] [PubMed] [Google Scholar]
- Hugo F., Mazurek S., Zander U., Eigenbrodt E. In vitro effect of extracellular AMP on MCF-7 breast cancer cells: inhibition of glycolysis and cell proliferation. J Cell Physiol. 1992 Dec;153(3):539–549. doi: 10.1002/jcp.1041530315. [DOI] [PubMed] [Google Scholar]
- Kaplan O., Cohen J. S. Metabolism of breast cancer cells as revealed by non-invasive magnetic resonance spectroscopy studies. Breast Cancer Res Treat. 1994;31(2-3):285–299. doi: 10.1007/BF00666161. [DOI] [PubMed] [Google Scholar]
- Katabi M. M., Chan H. L., Karp S. E., Batist G. Hexokinase type II: a novel tumor-specific promoter for gene-targeted therapy differentially expressed and regulated in human cancer cells. Hum Gene Ther. 1999 Jan 20;10(2):155–164. doi: 10.1089/10430349950018959. [DOI] [PubMed] [Google Scholar]
- Katzenellenbogen B. S., Kendra K. L., Norman M. J., Berthois Y. Proliferation, hormonal responsiveness, and estrogen receptor content of MCF-7 human breast cancer cells grown in the short-term and long-term absence of estrogens. Cancer Res. 1987 Aug 15;47(16):4355–4360. [PubMed] [Google Scholar]
- Kim J. W., Kim T. E., Kim Y. K., Kim Y. W., Kim S. J., Lee J. M., Kim I. K., Namkoong S. E. Antisense oligodeoxynucleotide of glyceraldehyde-3-phosphate dehydrogenase gene inhibits cell proliferation and induces apoptosis in human cervical carcinoma cell lines. Antisense Nucleic Acid Drug Dev. 1999 Dec;9(6):507–513. doi: 10.1089/oli.1.1999.9.507. [DOI] [PubMed] [Google Scholar]
- Lassen U., Daugaard G., Eigtved A., Damgaard K., Friberg L. 18F-FDG whole body positron emission tomography (PET) in patients with unknown primary tumours (UPT). Eur J Cancer. 1999 Jul;35(7):1076–1082. doi: 10.1016/s0959-8049(99)00077-5. [DOI] [PubMed] [Google Scholar]
- Lobo C., Ruiz-Bellido M. A., Aledo J. C., Márquez J., Núez De Castro I., Alonso F. J. Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells. Biochem J. 2000 Jun 1;348(Pt 2):257–261. [PMC free article] [PubMed] [Google Scholar]
- Lowe V. J., Naunheim K. S. Current role of positron emission tomography in thoracic oncology. Thorax. 1998 Aug;53(8):703–712. doi: 10.1136/thx.53.8.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mankoff D. A., Bellon J. R. Positron-emission tomographic imaging of cancer: glucose metabolism and beyond. Semin Radiat Oncol. 2001 Jan;11(1):16–27. doi: 10.1053/srao.2001.18100. [DOI] [PubMed] [Google Scholar]
- Mathupala S. P., Heese C., Pedersen P. L. Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J Biol Chem. 1997 Sep 5;272(36):22776–22780. doi: 10.1074/jbc.272.36.22776. [DOI] [PubMed] [Google Scholar]
- Mazurek S., Eigenbrodt E., Failing K., Steinberg P. Alterations in the glycolytic and glutaminolytic pathways after malignant transformation of rat liver oval cells. J Cell Physiol. 1999 Oct;181(1):136–146. doi: 10.1002/(SICI)1097-4652(199910)181:1<136::AID-JCP14>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
- Pagliassotti M. J., Donovan C. M. Role of cell type in net lactate removal by skeletal muscle. Am J Physiol. 1990 Apr;258(4 Pt 1):E635–E642. doi: 10.1152/ajpendo.1990.258.4.E635. [DOI] [PubMed] [Google Scholar]
- Petch D., Butler M. Profile of energy metabolism in a murine hybridoma: glucose and glutamine utilization. J Cell Physiol. 1994 Oct;161(1):71–76. doi: 10.1002/jcp.1041610110. [DOI] [PubMed] [Google Scholar]
- Racker E. Why do tumor cells have a high aerobic glycolysis? J Cell Physiol. 1976 Dec;89(4):697–700. doi: 10.1002/jcp.1040890429. [DOI] [PubMed] [Google Scholar]
- Rodríguez-Enríquez S., Torres-Márquez M. E., Moreno-Sánchez R. Substrate oxidation and ATP supply in AS-30D hepatoma cells. Arch Biochem Biophys. 2000 Mar 1;375(1):21–30. doi: 10.1006/abbi.1999.1582. [DOI] [PubMed] [Google Scholar]
- Rostom A. Y., Powe J., Kandil A., Ezzat A., Bakheet S., el-Khwsky F., el-Hussainy G., Sorbris R., Sjoklint O. Positron emission tomography in breast cancer: a clinicopathological correlation of results. Br J Radiol. 1999 Nov;72(863):1064–1068. doi: 10.1259/bjr.72.863.10700822. [DOI] [PubMed] [Google Scholar]
- Schiepers C., Hoh C. K. Positron emission tomography as a diagnostic tool in oncology. Eur Radiol. 1998;8(8):1481–1494. doi: 10.1007/s003300050579. [DOI] [PubMed] [Google Scholar]
- Schönekess B. O. Competition between lactate and fatty acids as sources of ATP in the isolated working rat heart. J Mol Cell Cardiol. 1997 Oct;29(10):2725–2733. doi: 10.1006/jmcc.1997.0504. [DOI] [PubMed] [Google Scholar]
- Singh A., Purohit A., Hejaz H. A., Potter B. V., Reed M. J. Inhibition of deoxyglucose uptake in MCF-7 breast cancer cells by 2-methoxyestrone and 2-methoxyestrone-3-O-sulfamate. Mol Cell Endocrinol. 2000 Feb 25;160(1-2):61–66. doi: 10.1016/s0303-7207(99)00256-7. [DOI] [PubMed] [Google Scholar]
- Stokes J. B., Grupp C., Kinne R. K. Purification of rat papillary collecting duct cells: functional and metabolic assessment. Am J Physiol. 1987 Aug;253(2 Pt 2):F251–F262. doi: 10.1152/ajprenal.1987.253.2.F251. [DOI] [PubMed] [Google Scholar]
- Ting Y. L., Sherr D., Degani H. Variations in energy and phospholipid metabolism in normal and cancer human mammary epithelial cells. Anticancer Res. 1996 May-Jun;16(3B):1381–1388. [PubMed] [Google Scholar]
- WARBURG O. On the origin of cancer cells. Science. 1956 Feb 24;123(3191):309–314. doi: 10.1126/science.123.3191.309. [DOI] [PubMed] [Google Scholar]
- Wahl R. L. Overview of the current status of PET in breast cancer imaging. Q J Nucl Med. 1998 Mar;42(1):1–7. [PubMed] [Google Scholar]
- Yutani K., Shiba E., Kusuoka H., Tatsumi M., Uehara T., Taguchi T., Takai S. I., Nishimura T. Comparison of FDG-PET with MIBI-SPECT in the detection of breast cancer and axillary lymph node metastasis. J Comput Assist Tomogr. 2000 Mar-Apr;24(2):274–280. doi: 10.1097/00004728-200003000-00017. [DOI] [PubMed] [Google Scholar]
- Zoubine M. N., Weston A. P., Johnson D. C., Campbell D. R., Banerjee S. K. 2-methoxyestradiol-induced growth suppression and lethality in estrogen-responsive MCF-7 cells may be mediated by down regulation of p34cdc2 and cyclin B1 expression. Int J Oncol. 1999 Oct;15(4):639–646. doi: 10.3892/ijo.15.4.639. [DOI] [PubMed] [Google Scholar]