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phosphorylation. The balance between glycolysis and various biological pathways involved in cancer initiation
oxidative phosphorylation is controlled by the relative and progression. The expression of MYC genes is
[49]
activities of two enzymes: pyruvate dehydrogenase (PDH) often elevated or deregulated in human neoplasms, and
and LDH. The activity of PDH is negatively controlled c-Myc seems to be at the crossroads of several important
by PDK-1, and HIF-1 can inactivate PDH by inducing pathways and processes involved in carcinogenesis.
PDK-1. Inactivation of PDH leads to suppression of MYC overexpression and promoter hypomethylation may
mitochondrial respiration. [27,28] HIF-1 also stimulates have a role in the gastric carcinogenesis process. MYC
expression of LDH-A, which facilitates the conversion of deregulation was mainly associated with poor prognostic
pyruvate into lactate, which decreases use of pyruvate features. [50]
[10]
by mitochondria and suppresses mitochondrial respiration.
In addition, HIF-1 can also modulate COX expression. The GLUT family proteins are glucose transporter-like
Under hypoxic conditions, the sub-unit composition of proteins that have been well characterized. The 14 GLUTs
COX is changed to optimize its activity. The expression are categorized into three classes based on sequence
of the COX4-2 sub-unit is increased and optimizes the similarity: Class 1 (GLUTs 1-4 and 14); Class 2 (GLUTs
activity of COX under aerobic conditions. [24] 5, 7, 9 and 11) and Class 3 (GLUTs 6, 8, 10, 12 and
HMIT). Several studies have been published on GLUT
[51]
Another important consequence of the glycolytic shift family members, especially GLUT 3, [52-54] but GLUT
in tumor cells is their acquired resistance to apoptotic 1 has been the main focus of the investigation. [55-57]
cell death. The two major apoptotic pathways include GLUT 1 comprises 492 amino acid residues and possesses
the extrinsic (receptor-mediated) pathway and the a single N-linked glycosylation site at N45, and its
[58]
intrinsic pathway. The extrinsic pathway engages crystal structure has been reported recently. GLUT
[59]
initiator pro-caspase-8, which activates pro-caspase-3 1 is transcriptionally regulated by HIF-1A and
[60]
and other effector caspases. The intrinsic pathway c-Myc. A recent investigation showed that GLUT 1 was
[61]
involves permeabilization of the outer mitochondrial upregulated in cells with KRAS or BRAF mutations,
[62]
membrane (OMM) followed by the release of and GLUT 1 expression in CRC cells was positively
cytochrome c and other proteins from the intermembrane correlated with FDG accumulation and KRAS/BRAF
space of mitochondria. Permeabilization of the OMM is mutation. MAPK signaling induces phosphorylation of
[63]
considered to be a crucial event during the early phase of Ser 37 in PKM2, and nuclear-phosphorylated PKM2 then
the apoptotic process. Multiple proteins, including B-cell induces c-Myc expression, resulting in the upregulation
lymphoma 2 (Bcl-2) family, [29,30] hexokinase, [31,32] Akt [33,34] of GLUT 1. Overexpression of GLUT 1 in a mammary
[64]
and loss of p53, [35,36] support the glycolytic shift. These tumor cell line with low levels of endogenous GLUT 1
proteins render tumor mitochondria less susceptible to results in both a decrease in apoptosis and an increase in
the permeabilization of the OMM and the mitochondrial proliferation. [65]
pathway of apoptosis.
Hexokinases catalyze the phosphorylation of glucose
Alteration of Protein Expression in the to glucose-6-phosphate (G6P). This is the fi rst and
Warburg Effect rate-limiting step in glucose metabolism. HK2 is one of
four members of the hexokinase family. The hexokinase
Cancer cells exhibit altered glucose metabolism, which isoenzymes (HK1, HK2, HK3 and glucokinase) are
is described by the increased uptake of glucose and the structurally similar; however, only HK1 and HK2 are
conversion of glucose to lactate in cancer cells under functionally similar. HK2, but not HK1, is overexpressed
adequate oxygen tension. HIF-1A and c-Myc transcription in several cancer types compared with normal
factors cooperatively induce a transcriptional program tissue, and overexpression of HK2 was reported in
for glycolysis by targeting many glycolytic enzyme hepatocellular carcinoma (HCC). [66-68] HK2 localizes to
genes, including HK2, PKM2, LDH-A and PDK-1. the outer membrane of the mitochondria and is the major
Key regulatory sub-units of HIF include HIF-1A and hexokinase isoform expressed in cancer cells. [69]
endothelial PAS domain protein 1 (EPAS1; HIF-2), and
these proteins are differentially overexpressed in cancer PK is a glycolytic enzyme that catalyzes a reaction
cells. [37,38] Many studies demonstrated that HIF-1A generating pyruvate and ATP from phosphoenolpyruvate
positive expression was signifi cantly associated with poor and ADP. Four isoforms of PK (L, R, M1 and M2)
outcome of diverse human cancers. [38-43] Low expression are present in mammals. Splicing of PKM is regulated
of HIF-1A may be associated with a favorable outcome by splicing repressors, and the expressions of those
of 5-fl uorouracil (5-FU)-based adjuvant chemotherapy repressors are induced by MYC oncoprotein. [70,71] M2 is
in gastric cancer patients. [44,45] High expression of expressed in embryonic cells, adult stem cells and
HIF-2A was associated with poor survival in gastric cancer cells and is necessary for aerobic glycolysis
cancer patients, but not colorectal cancer (CRC) and that this metabolic phenotype provides a selective
[46]
[72]
patients. [42,47] The MYC protein affects the expression of growth advantage for cancer cells in vivo. Mutation
approximately 15% of the genes in the human genome, of the S37 ERK phosphorylation site in PKM2 blocked
[48]
and thus MYC deregulation may result in alterations in translocation of PKM2 to the nucleus, which suggested
[64]
174 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦