intermediary metabolism in...

INTERMEDIARY METABOLISM IN CANCER

2010

Michael Lea

Intermediary Metabolism - Lecture Outline

• Glycolysis and respiration in cancer cells• Convergence and deletions • Correlation of biochemical parameters with tumor

growth• Polyamines

GLYCOLYSIS AND RESPIRATION IN CANCER CELLS

The first metabolic pathways to be studied in cancer cells were those of glycolysis and cell respiration. Otto Warburg studied these parameters using tissue slices incubated in a bicarbonate buffer in flasks attached to a manometer. By incubating in media gassedwith either 95% oxygen/5% CO2 or 95% nitrogen/5% CO2 it was possible to measure glycolysis under aerobic or anaerobic conditions. The production of lactic or pyruvic acids causes the release of CO2from the bicarbonate buffer. Quotients were measured for aerobicglycolysis (QL O2), anaerobic glycolysis (QL N2) and respiratory activity (QO2).

The data indicated that, in general, glycolysis was greater in malignant than in non-malignant tissues. This was more marked under aerobic than anaerobic conditions. This difference suggested that the Pasteur effect was greater in normal tissues. It should be noted that there is an overlap of values in Warburg’s data.

Table 15.2 Condensed Tumor Metabolism Data of Warburg, Burk, and OthersSee H.C. Pitot, Fundamentals of Oncology, 4th edition, page 645

Tissue Respiration Anerobic AerobicGlycolysis Glycolysis

Normal animal tissues 9.3 7.2 2.1(3-21) (2-19) (0-10)

Animal neoplasms 11.8 25.6 14.0(5.3-19.8 (14.0-34.8) (4.7-24.6)

Human neoplasms 5.3 20.5 13.3(2-6) (13-29) (5-19)

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CONVERGENCE AND DELETIONS

• Warburg concluded that cancer originated from an irreversible injury of respiration

• Greenstein noted that many tumors showed a convergence in their metabolic patterns

• In 1947 the Millers suggested that carcinogenesis results from “a permanent alteration or loss of proteins essential for the control of growth.”

• Studies by Weber on the Morris series of chemically induced hepatomas in rats led to the Molecular Correlation Concept in which some biochemical parameters are viewed as correlating with tumor growth. (Reference; G. Weber, New England J. Med. 296: 486 and 541, 1977)

UPREGULATION OF GLYCOLYSIS LEADS TO MICROENVIRONMENTAL ACIDOSIS

Clinical use of 18fluorodeoxyglucose positron-emission tomography (FdG PET) has demonstrated that increased glucose uptake is observed in most human cancer.

Increased FdG uptake occurs because of upregulation of glucose transporters, notably GLUT1 and GLUT3, and results in increased glycolysis.

Increased glycolysis results in microenvironmental acidosis and requires further adaptation through somatic evolution to phenotypes resistant to acid-induced toxicity.

Reference: R.A. Gatenby and R.J. Gillies. Why do cancers have high aerobic glycolysis? Nature Reviews Cancer 4: 891-899, 2004.

INHIBITING GLYCOLYSIS• A lack of tumor-specific inhibitors of glycolysis has

historically prevented glycolysis being used as a chemotherapeutic target.

• Glycolysis can be activated by an increase in the concentration of fructose 2,6-bisphosphate which activates the rate-limiting enzyme phosphofructokinase 1.

• Fructose 2,6-bisphosphate is produced by the bifunctional enzyme phosphofructokinase 2/ fructose 2,6-bisphosphatase (PFKFB).

• The inducible PFKFB3 isozyme is constitutively expressed by many tumor cells.

• A small molecule inhibitor of PFKFB3 has been reported to inhibit the growth of tumors in mice.

• Reference: Clem et al., Mol. Cancer Ther. 7: 110120, 2008)

POLYAMINES

Polyamines are organic cations formed by the enzymatic decarboxylation of ornithine to yield putrescine and by further additions from decarboxylated S-adenosyl methionine to form spermidine and spermine.

Ornithine decarboxylase and polyamine content are increased in many carcinomas including skin and colon cancer.

DFMO (difluoromethylornithine) is an inhibitor of ornithine decarboxylase and has some antitumor action.

Polyamines work at least in part by regulating specific gene expression

Reference: E.W. Gerner and F.L. Meyskens. Polyamines and cancer: old molecules, new understanding. Nature reviews Cancer 4: 781-792, 2004.

INTERMEDIARY METABOLISM -SUGGESTED READING

• R.W. Ruddon, In Holland-Frei Cancer Medicine - 6th Ed, Part II, Section 1, 9. Biochemistry of Cancer (2003)