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Gene & Protein in Disease Opportunities and challenges of HIF-1 in cancer

glycolysis. HIF-1 enhances glucose transporters, mainly HIF-1 also suppresses the enzyme responsible for pyruvate
glucose transporters 1 and 4, and activates genes coding decarboxylation through a series of reactions. Consequently,
for glycolytic enzymes. The HIF-1-dependent Warburg there is insufficient acetyl-CoA to participate in the
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effect is critically important, as increased expression of Krebs cycle within the mitochondria. HIF-1, further,
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HIF-1α is prevalent in solid tumors such as colon, prostate, hinders mitochondrial functions through the elimination
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lung, breast, and stomach cancer. In addition, HIF-1 can of proteins associated with mitochondrial activity. This
induce angiogenesis when activated by lactate uptake in the impairment is achieved through the regulation of certain
cells and activate the pentose phosphate pathway (PPP). microRNAs, which targets and suppresses the expression
Specific biochemical and molecular mechanisms by which of the mRNAs encoding these proteins. In addition, HIF-1
HIF-1 influences cancer cell metabolism, and behavior are can affect the mitochondrial population by hindering the
analyzed in the subsequent subsections. biogenesis of new organelles and initiating mitochondrial
autophagy. Figure 1 summarizes mitochondrial metabolic
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1.3.1. Effect of HIF-1 on angiogenesis pathways associated with HIF-1.
Cells produce and secrete lactate as the final product of
lactic acid fermentation, which occurs after glycolysis. 1.3.5. HIF-1-induced overexpression of programmed
Cancer cells absorb lactate and convert it to pyruvate, death ligand-1 (PD-L1)
thus increasing its intracellular concentration. Increased HIF-1 is responsible for the increased expression of
pyruvate levels lead to reduced HIF-1 degradation and, PD-L1 on the surface of cancer cells. PDL-1 binds to its
consequently, enhanced HIF-1 activity, promoting tumor receptor, programmed cell death protein 1 (PD-1), which
angiogenesis. 15 is expressed by T-cells. This interaction enables cancer
cells to evade immune system surveillance and promotes
1.3.2. Effect of HIF-1 on the PPP cancer cell proliferation by hindering cytotoxic T-cell
Pyruvate kinase M2 (PKM2) is a HIF-1-dependent infiltration. 19
glycolytic enzyme that regulates PPP. In comparison
to other pyruvate kinase (PK) complexes, PKM2 is less 2. Overview of HIF-1
effective at converting phosphoenolpyruvate to pyruvate. 2.1. Biological role and functions of HIF-1
Therefore, glucose-6-phosphate, an intermediate glycolysis Cancer progression is driven by complex intercellular
metabolite, accumulates and is supplied to PPP. This signaling networks between tumor and stromal cells. The
pathway produces pentoses, which are used as raw material TME is specific in terms of its internal conditions, with
to create nucleotides and NADPH. NADPH can then be hypoxia being one of the most common and contributing
utilized for the production of anti-oxidant glutathione-SH significantly to tumor aggressiveness. Cells adapt to the
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(GSH), thereby granting cancer cells antioxidant hypoxic environment through a family of transcription
capabilities and resistance to radiotherapy. 15 factors known as HIFs. One particular member with a
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1.3.3. HIF-1-dependent reprogramming of the glucose well-established role in cancer progression is HIF-1. This
metabolic pathway protein synchronizes the activities of many transcription
factors and signaling molecules that collectively influence
For glycolysis to occur, glucose must be taken up by tumorigenesis.
glucose transporters (GLUTs). HIF-1 regulates the
expression of GLUT1 and, combined with the hypoxic HIF-1 is a heterodimer, consisting of an oxygen-
environment of the tumor, enhances glucose uptake, regulated α subunit and an oxygen-independent β
thus reinforcing aerobic glycolysis. The pyruvate derived subunit (also called aryl hydrocarbon receptor nuclear
from glycolysis is downstream processed into lactate translocator). It binds to the promoter regions of target
through lactic fermentation, instead of acetyl coenzyme A genes containing hypoxia-responsive elements (HREs;
(CoA), with the help of lactate dehydrogenase A (LDH- 5’-RCGTG-3’, where R = A or G), further stimulating the
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A), whose expression is also affected by HIF-1. Lactic expression of different genes. Together with its partners,
acid fermentation is essential for glycolysis as it produces HIF-1 is involved in various cancer hallmarks, such as
NAD , a necessary coenzyme for a glycolytic reaction. 15 angiogenesis, migration, invasion, generation of CSCs, pH
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regulation, and glucose metabolism. 24
1.3.4. HIF-1-induced decline in mitochondrial function
Moreover, HIF-1 plays an essential role in the
Activation of HIF-1 results in decreased acetyl-CoA levels inflammatory process of immune cells. During
since pyruvate partakes in aerobic glycolysis instead of extravasation from the bloodstream to the inflammation
pyruvate decarboxylation, which produces acetyl-CoA. site, immune cells are suddenly exposed to hypoxic

Volume 3 Issue 2 (2024) 3 doi: 10.36922/gpd.3431