Download INTERMEDIARY METABOLISM IN CANCER

INTERMEDIARY METABOLISM IN
CANCER
MOLECULAR ONCOLOGY
2017
Michael Lea
Intermediary Metabolism - Lecture Outline
• Glycolysis and respiration in cancer cells
• Convergence and deletions
• Correlation of biochemical parameters with tumor
growth
• Polyamines
Hallmarks of Cancer: The Next
Generation
Hanahan and Weinberg
Cell 144: 646 2011
HISTORY OF ONCOLOGY - 4
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 gassed
with 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 CO2
from the bicarbonate buffer. Quotients were measured for aerobic
glycolysis (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.
For debate see Science, 124: 267-272, 1956
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: 110-120, 2008
Levine and
Puzio-Kuter
Science 330:
1340-1344.
2010
TIGAR: TP53 induced glycolysis and apoptosis regulator
ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promote the Warburg
effect
Pyruvate kinase M2 (PKM2) is upregulated in multiple cancer types and
contributes to the Warburg effect by unclear mechanisms. EGFR-activated
ERK2 binds directly to PKM2 and phosphorylates PKM2 at Ser 37, but does not
phosphorylate PKM1. Phosphorylated PKM2 Ser 37 recruits PIN1 for cis-trans
isomerization of PKM2, which promotes PKM2 binding to importin a5 and
translocating to the nucleus. Nuclear PKM2 acts as a coactivator of beta-catenin
to induce c-Myc expression, resulting in the upregulation of GLUT1, LDHA and,
in a positive feedback loop, PTB-dependent PKM2 expression. Replacement of
wild-type PKM2 with a nuclear translocation-deficient mutant (S37A) blocks the
EGFR-promoted Warburg effect and brain tumour development in mice. In
addition, levels of PKM2 Ser 37 phosphorylation correlate with EGFR and
ERK1/2 activity in human glioblastoma specimens. These findings suggest the
importance of nuclear functions of PKM2 in the Warburg effect and
tumorigenesis.
Reference: Yang, W et al., Nature Cell Biol. 14: 1295 (2012)
IDH mutations and cancer
Mutations in isocitrate dehydrogenase 1 and 2 result
in the formation of 2-hydroxyglutarate (2HG) instead
of alpha-ketoglutarate. 2HG is a competitive inhibitor
of alpha-ketoglutarate-dependent dioxygenases.
Dioxygenases have an important role in
demethylation reactions for histones and DNA
causing hypermethylation in glioma and AML.
•
Reference: Yen KE and Schenkein DP: Cancer-associated isocitrate
dehydrogenase mutations. The Oncologist 17: 5-5, 2012
Fumarate hydratase
Low activities of fumarate hydratase (fumarase)
drives a metabolic shift to aerobic glycolysis in some
kidney tumors and thereby enhances the Warburg
effect in which aerobic glycolysis tends to be
increased in cancer cells
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 and R.W. Kufe, In Holland-Frei
Cancer Medicine - 8th Ed, Part II, Section 1,
9. Biochemistry of Cancer (2010)
• A.J. Levine and A.M. Puzio-Kuter. The control
of the metabolic switch in cancers by
oncogenes and tumor suppressor genes.
Science 330: 1340-1344, 2010.
• M.D. Hirschey et al., Dysregulated
metabolism contributes to oncogenesis.
Seminars in Cancer Biology 35: S129-S150,
2015