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Topic: Reviews of Recent Advances in Research and Treatment for
Gastroenterological Malignancies

Cancer metabolism in gastrointestinal cancer

Hiroshi Sawayama , Nobutomo Miyanari , Hideo Baba 2
1
1
1 Department of Surgery, National Hospital Organization Kumamoto Medical Center, 1-5 Ninomaru, Kumamoto 860-0008, Japan.
2 Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556,
Japan.
Correspondence to: Prof. Hideo Baba, Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University,
1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: hdobaba@kumamoto-u.ac.jp

ABSTRACT
Cancer cells exhibit altered glucose metabolism, mitochondrial dysfunction, anaerobic glycolysis and upregulation of the pentose
phosphate pathway (PPP). Recent genetic and metabolic analyses have provided insights into the molecular mechanisms of genes
that are involved in the alteration of cancer metabolism and tumorigenesis. Hypoxic induced factor 1 regulates the reciprocal
relationship between glycolysis and oxidative phosphorylation, and p53 also modulates the balance between the glycolytic pathway
and oxidative phosphorylation. Mitochondria function in cancer differs from that in normal cells owing to mutations of mitochondrial
DNA and alterations of metabolism. Overexpression of transcription factors, metabolite transporters and glycolytic enzymes is
observed and associated with poor prognosis, and it may be associated with chemoradiotherapy resistance in multiple cancer cell
types. The PPP plays a critical role in regulating cancer cell growth by supplying cells with ribose-5-phosphate and nicotinamide
adenine dinucleotide phosphate for detoxifi cation of intra-cellular reactive oxygen species (ROS), reductive biosynthesis and
ribose biogenesis. ROS levels increase during carcinogenesis owing to metabolic aberrations. This review discusses alterations
of mitochondrial metabolism, anaerobic glycolysis, the PPP and control of ROS levels by the endogenous anti-oxidant system in
cancer, as well as the novel small molecules targeting these enzymes or transporters that exert anti-proliferative effects.
Key words: Anti-oxidants, cancer metabolism, mitochondria, pentose phosphate pathway, reactive oxygen species, Warburg effect

Introduction fl avin adenine dinucleotide (FADH2) (reduced form
of FADH2) to the respiratory chain complexes in
In 1926, Otto Warburg found the conversion of mitochondria. The electron transfer system generates
glucose to lactic acid in the presence of adequate 36 ATP molecules per glucose across the mitochondrial
oxygen as a specific metabolic abnormality of cancer inner membrane. Under limited oxygen conditions, such
cells. [1,2] Warburg further hypothesized that cancer as muscles under prolonged exercise, pyruvate is not
results from a defect of mitochondrial metabolism that used in the TCA cycle and is converted into lactic acid
leads to aerobic glycolysis. The role of dysfunctional by lactate dehydrogenase (LDH) in a process termed
glucose metabolism in cancer is now firmly anaerobic glycolysis.
established. Recent genomic and proteomic research
has provided insights into the molecular mechanisms Recent genetic and metabolic analyses have provided
of cancer metabolism. insights into the molecular mechanisms of the genes that
contribute to anaerobic glycolysis and tumorigenesis.
Two main pathways generate adenosine The direct mechanistic links between activated
triphosphate (ATP) required for cell proliferation and oncogenes and altered glucose metabolism are regulated
survival. The fi rst is glycolysis, which metabolizes by phosphoinositide 3-kinase (PI3K), Akt, p53, [5,6]
[4]
[3]
glucose to pyruvate in the cytoplasm to produce a AMP-activated protein kinase (AMPK), [3,7] c-Myc
net two ATP molecules from each glucose molecule. and hypoxia-inducible factor (HIF). The c-Myc and
The other is the tricarboxylic acid (TCA) cycle, HIF-1A transcription factors target many of the same
which uses pyruvate formed from glycolysis glycolytic enzyme genes, including hexokinase 2 (HK2),
to donate electrons via nicotinamide adenine
dinucleotide (NADH) (reduced form of NADH) and This is an open access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows
others to remix, tweak, and build upon the work non-commercially, as long as
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How to cite this article: Sawayama H, Miyanari N, Baba H. Cancer
metabolism in gastrointestinal cancer. J Cancer Metastasis Treat
DOI: 2015;1:172-82.
10.4103/2394-4722.165533
Received: 13-07-2015; Accepted: 29-07-2015.

172 © 2015 Journal of Cancer Metastasis and Treatment ¦ Published by Wolters Kluwer - Medknow