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that PKM2 moves into the nucleus as a monomer. Fructose-6-phosphate is isomerized to G6P in cells,
Tumor cells have multiple ways to regulate PKM2 for and this accumulated G6P is diverted into the PPP, an
cell growth and survival, including controlling PKM2 alternative metabolic pathway that can provide substrates
expression, localization, post-translational modifi cation for the later steps in glycolysis. Glucose-6-phosphate
and allosteric regulation. PKM2 also has non-metabolic dehydrogenase (G6PD) is mediated by various signals,
functions as a transcriptional coactivator and protein and it acts as a sensor of cellular NADP levels.
+
kinase. PKM2 is considered an attractive target for cancer Increased NADP activates G6PD by competing with
+
treatment. Further studies are needed before inhibitors NADPH for binding to this enzyme (G6PD), and
[73]
and activators of PKM2 can be used as therapeutic determines the amount of NADPH by controlling the
interventions. [74] metabolism of glucose via the PPP. The increased
[85]
fl ow through the PPP lowers apoptosis because of an
PDK regulates PDH, which links glycolysis to the TCA
cycle by reversible phosphorylation. Phosphorylation of increased generation of reduced GSH and removal of
[25]
PDH by PDK inactivates PDH and halts pyruvate use in ROS in cells. Elevated levels of G6PD in association
[75]
the TCA cycle. Four PDK isoforms have been verifi ed with higher levels of PPP-derived metabolites suggest a
in human tissue, and the expression of these isoforms prominent role of this pathway in metabolic alterations
[86,87]
was organ specifi c. PDK-1 positivity was associated with of human cancer. G6PD inhibition decreases cancer
poor prognosis in gastric cancer; however, expression cell survival, NADPH levels and increases production
[76]
of PDK-1 was decreased in colon cancer compared of ROS, suggesting that the PPP plays an important role
[88,89]
to normal tissue. PDK-3 expression was detected in in the regulation of redox homeostasis. G6PD is
colon cancer, and PDK-3 positivity was associated with associated with adriamycin resistance in breast cancer
[90]
[77]
poor prognosis. Only a few studies have reported the cells using proteomics analysis.
relation between PDK positivity and prognosis, and the The PPP is positively regulated by K-ras G12D , PI3K,
[91]
clinical signifi cance of PDK expression has remained mTORC1, Tap73, [93,94] HSP27, SREBP, the
[92]
[95]
[92]
unclear. LDH is a tetrameric enzyme comprising two ataxia-telangiectasia mutated kinase, protein kinase
major sub-units, A and/or B, resulting in fi ve isozymes A, NADP and glycolytic inhibition (TIGAR, PKM2
[25]
(A4, A3B1, A2B2, A1B3 and B4) that can catalyze and PGAM). The PPP is negatively regulated by p53,
the forward and backward conversion of pyruvate to PTEN, AMPK, cyclic adenosine monophosphate,
[3]
[96]
lactate. LDH-A (LDH-5, MLDH or A4), which is the cyclic AMP-response element modulator and
predominant form in skeletal muscle, kinetically favors aldosterone. TAp73, the transcriptionally competent
[97]
the conversion of pyruvate to lactate, controlling the isoform of the p53 family protein p73, was identifi ed as a
conversion of pyruvate to lactate of the cellular glycolytic transcriptional regulator of G6PD. [94]
process. Many studies have shown that human cancers
[78]
have higher LDH-A levels compared with normal The PPP is a well-established metabolic pathway, but
[79]
tissues. Previous studies showed that 661 intestinal-type the mechanism that activates the PPP has yet to be
[80]
gastric cancer (ITGC) and 128 CRC specimens identifi ed. TIGAR, a target of p53, inhibits glycolysis
[81]
with high LDH-A expression are associated with poor and diverts the carbon fl ux into the PPP, resulting in the
prognosis. LDH-A is specifi cally phosphorylated at Y10 passive promotion of PPP activity. NADPH production
in various cancer cell lines, head and neck squamous cell pathway is targeted by nuclear factor E2 p45-related
[98]
carcinoma ( SCC), lung cancer, breast cancer and prostate factor 2 (Nrf2). Nrf2, a bZIP transcription factor,
cancer cells and by diverse oncogenic tyrosine kinases, plays a central role in the regulation (basal and/or
including FGFR1, ABL, JAK2 and FLT. LDH-A inducible expression) of phase 2 genes by binding to
[82]
reduction using si-RNA for LDH-A can suppress the the anti-oxidant response element in their promoters.
tumorigenicity of ITGC cells and HCC. [83] A previous study focused on the cytoprotective aspect
[80]
of the PPP by analyzing NADPH production as reducing
The Pentose Phosphate Pathway equivalents for ROS elimination. The PPP genes are
[99]
strongly activated by Nrf2 in proliferating cells in which
The PPP is a major pathway for glucose catabolism. the PI3K-Akt pathway is active, and increased expression
Glucose is a common fuel for multicellular organisms, of the PPP genes contributes to cell proliferation. [98]
entering cells through GLUTs and then being
phosphorylated by HK to form G6P. G6P can be further Under basal conditions, Keap1 binds to the ETGE
metabolized by both the glycolytic pathway and the and DLG motifs in Nrf2 and recruits Nrf2 to the
PPP. The PPP generates ribose 5-phosphate (R5P), Keap1-Cul3-E3 ubiquitin ligase complex, leading
[84]
a critical sub-strate for nucleotide synthesis. The PPP to ubiquitination and subsequent degradation of
plays a critical role in regulating cancer cell growth by Nrf2. Oxidative stress or electrophiles can cause a
supplying cells with not only R5P but also NADPH conformational change in the Keap1-Cul3-E3 ubiquitin
for detoxifi cation of intra-cellular ROS, reductive ligase by acting on specifi c cysteine residues in
biosynthesis and ribose biogenesis. Keap1. [100] These changes disrupt Nrf2-Keap1 binding at
Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 175