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pyruvate kinase type M2 (PKM2), LDH-A and pyruvate show an embryonic lethal phenotype and SOD2 KO
[15]
dehydrogenase kinase, isozyme 1 (PDK-1). mice die within 3 weeks of birth because of mitochondrial
oxidative damage and severe neurodegeneration. [16,17]
The pentose phosphate pathway (PPP) is a major pathway
for glucose catabolism. The PPP directly or indirectly Mutations in mitochondrial DNA (mtDNA) occur at a
provides reducing power to fuel the biosynthesis of high frequency in human tumors. Tumor mtDNA somatic
lipids and nucleotides and sustains anti-oxidant responses mutations range from severe insertions/deletions and
to support cell survival and proliferation. Abnormal chain termination mutations to mild missense mutations.
respiratory metabolic pathways infl uence energy balance A total of 190 tumor-specifi c somatic mtDNA mutations
and the reactive oxygen species (ROS) balance in cancer have been reported and 72% of them are also mtDNA
cells. The increase in ROS generation from metabolic sequence variants found in the general population.
abnormalities and oncogenic signaling in cancer cells They include 52% tumor somatic mRNA missense
triggers a redox adaptation response to maintain ROS mutations, 83% tRNA mutations, 38% rRNA mutations
levels below the toxic threshold. Cancer cells would be and 85% control region mutations. Germline mtDNA
increasingly dependent on the anti-oxidant system. mutations at nucleotides 10,398 and 16,189 have been
associated with breast cancer, esophageal cancer
[18]
[19]
In this review, signifi cant molecular insights into and endometrial cancer. The mtDNA conferring high
[20]
mitochondrial metabolism, anaerobic glycolysis and the metastatic potential contained G13997A and 13885insC
PPP in cancer are discussed. We also review the control mutations in the gene encoding NADH dehydrogenase
of ROS levels by the endogenous anti-oxidant system and sub-unit 6. These mutations produced a defi ciency in
the therapeutic strategies targeting cancer metabolism. respiratory complex I activity and were associated with
[21]
overproduction of ROS. Severe mutations can inhibit
Mitochondria in Cancer Cells
oxidative phosphorylation, increase ROS production and
As the main energy producers, mitochondria produce promote tumor cell proliferation; milder mutations may
ATP using the TCA cycle and oxidative phosphorylation. permit tumors to adapt to new environments. [22]
However, they also generate ROS during this process, Recent investigations have revealed that p53 can
which are harmful to the cell if produced in excess. modulate the balance between the glycolytic pathway
In addition, mitochondria play a crucial role in the and mitochondrial oxidative phosphorylation. The key
[23]
regulation of cell death pathways and intra-cellular component in this regulation is the gene encoding synthesis
Ca homeostasis. Mitochondria activate apoptosis by of cytochrome c oxidase 2 (SCO2), in conjunction with
2+
regulating the release of pro-apoptotic proteins from the the SCO1 protein. Analysis of potential p53 target genes
mitochondrial intermembrane to the cytosol, and they that can infl uence mitochondrial function showed that
also play a crucial role in non-apoptotic cell death. SCO2, but not SCO1, was induced in a p53-dependent
[8]
Key regulators related to cell death in the mitochondria manner. SCO2 is critical for regulating the cytochrome
[9]
are frequently altered in cancer cells, and the function c oxidase (COX) complex, the major site of oxygen use
of mitochondria in cancer cells is different from that in and is required for the assembly of COX. Mutation of
[24]
normal cells. [10] p53 in tumor cells leads to inhibition of mitochondrial
The mitochondrial mechanism in cancer cells is different respiration as a result of COX defi ciency and a shift of
from that in normal cells using oxidative phosphorylation. cellular energy metabolism toward glycolysis. Inhibition
In oxidative phosphorylation, ATP synthesis requires of glycolysis by glucose withdrawal leads to the activation
signifi cant amounts of oxygen, which leads to the of p53. Under conditions of cellular stress, activation
continuous production of ROS such as superoxide of p53 could increase SCO2 expression and stimulate
anion, organic peroxide and hydrogen peroxide. If mitochondrial respiration and ATP production. Another
[11]
the redox regulating system does not eliminate the newly discovered target of p53 is TP53-induced glycolysis
generated ROS, the excessive ROS may cause cellular and apoptosis regulator (TIGAR). Expression of TIGAR
damage. Mitochondria have redox defense systems for lowered fructose-2,6-bisphosphate levels in cells, resulting
the elimination of hydrogen peroxide. Glutathione (GSH) in the inhibition of glycolysis while stimulating NADPH
[25]
and glutathione peroxidases require nicotinamide adenine generation through the pentose phosphate shunt. The
dinucleotide phosphate (NADPH) for the elimination of expression of TIGAR in primary tumors is signifi cantly
H O and other peroxides generated in the mitochondria. correlated with standardized uptake values max, and
2
2
The mitochondrial complex V (ATP synthase) produces low expression of TIGAR may predict a worse clinical
[26]
ATP from ADP and inorganic phosphate. As an outcome in patients with non-small cell lung cancer.
anti-oxidant defense system, peroxiredoxin (Prx) 3, HIF-1 plays an important role in the upregulation of
Prx5, superoxide dismutase 2 (SOD2) and thioredoxin enzymes stimulating glucose use. Recent investigations
2 eliminate ROS produced in mitochondria. [12,13] Prx3 demonstrated that HIF-1 suppresses mitochondrial
knockout (KO) mice exhibit metabolic dysregulation and function in tumor cells and modulates the reciprocal
[14]
induction of oxidative damage, thioredoxin 2 KO mice relationship between glycolysis and oxidative
Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 173