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

to the literature, the majority of cancer types exhibit the HIF-1 is recognized as one of the most important
Warburg effect, making it crucial to understand its nature proteins related to the Warburg effect. Structurally,
and underlying mechanisms to develop novel treatments HIF-1 is a heterodimer composed of HIF-1α and HIF-1β
aimed at improving the overall survival and quality of life subunits. The relatively unstable HIF-1α subunit is heavily
for cancer patients. regulated by oxygen levels; it is hydroxylated by oxygen-
One of the most studied mechanisms in cancer dependent prolyl hydroxylase domain proteins (PHDs),
progression is the Warburg effect. This term, named after which triggers a sequence of reactions that lead to its
the scientist Otto Warburg, describes the abnormal and degradation. In hypoxic environments, HIF-1α cannot be
unprecedented increase in glucose uptake by cancer cells, hydroxylated; thus, it is stabilized and transported to the
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which is, in turn, utilized for glycolysis under aerobic nucleus, where it binds with HIF-1β subunits. HIF-1β,
conditions. Glycolysis is a significantly less efficient commonly referred to as aryl hydrocarbon receptor nuclear
metabolic process in contrast to aerobic respiration translocators, is expressed constantly and independently of
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but sustains energy for intensive metabolic processes. oxygen concentration. Given the regulated expression of
However, when high adenosine triphosphate (ATP) levels HIF-1α, our literature review focuses on this subunit.
are present, mitochondrial function is suppressed due Functionally, HIF-1 acts as a transcription factor and
to limited glycolysis. These cancer cells may also trigger is one of the key moderators of genes related to hypoxia
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neighboring stromal cells to undergo aerobic glycolysis metabolic pathways, angiogenesis, inflammation, tumor
and transfer metabolites back to the originating cancer development, and proliferation in physiologically
cells through a process known as the reverse Warburg unfavorable conditions. Several metabolic pathways lead
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effect. 7 to the activation and/or upregulation of HIF-1 in cancer
The metabolic reprogramming associated with the cells, such as the phosphoinositide 3-kinase (PI3K)/Akt/
Warburg effect enables cancer cells to enhance their protein kinase C (PKC)/histone deacetylase (HDAC)
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survival under unfavorable conditions, evade the immune pathway. Once activated, the HIF-1 complex assembles
system, and resist treatment. Metabolites, such as lactate, and translocates to the cell nucleus to trigger Warburg-
and the resulting acidic environment contribute to immune related pathways, as further analyzed in this literature
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evasion, as analyzed below. In addition, cancer cells can review.
acquire chemoresistance through several mechanisms, 1.3. The significance of the HIF-1-dependent
such as the regulation of apoptosis, glucose uptake in Warburg effect
glycolysis, stress response, and detoxification, particularly
in cancer stem cells (CSCs). 8 Glucose is the main energy source for both normal and
cancer cells. Normal cells metabolize glucose through
1.2. The human hypoxia-inducible factor (HIF) family glycolysis, followed by oxidative phosphorylation through
and the link between HIF-1 and the Warburg Effect the Krebs cycle, a process that occurs exclusively under
The HIF family consists of transcription factors that regulate limited oxygen supply in normal cells. However, the tumor
genes commonly associated with hypoxic conditions. microenvironment (TME) is hypoxic due to the inability of
These genes are involved in angiogenesis, cell growth existing blood vessels to supply tumor cells with sufficient
and cycle, and cellular and systemic metabolism. The oxygen and nutrients. Consequently, cancer cells adapt by
primary members of the HIF family are HIF-1α, HIF-2α, reprogramming their metabolism to favor glycolysis even
and HIF-3α, all of which heterodimerize with HIF-1β, as in the presence of abundant oxygen, a phenomenon known
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further analyzed in the subsequent sections. Each member as aerobic glycolysis or the Warburg effect.
has distinct roles and distribution. HIF-1 is the most Many factors contribute to the metabolic
widely distributed and plays a significant role in processes reprogramming of cancer cells, such as oncogene
related to acute hypoxia, such as sugar metabolism, activation, underexpression of tumor suppressor genes,
vascularization, and erythropoiesis. In contrast, HIF-2 and and overexpression of growth factor receptor genes,
HIF-3 have more limited distributions and are located in occasionally combined with epigenetic changes. These
specific tissues. HIF-2 is involved in chronic hypoxia, while changes result from irregular cell signaling. 16,17 Specifically,
HIF-3 acts as an antagonist of the other HIFs by competing the overexpression of HIF-1, a transcription factor that
for the HIF-1β binding site. Although this article primarily regulates the expression of genes responsible for the
focuses on the role and function of HIF-1α in cancer, it synthesis of proteins partaking in glucose metabolism,
is important to note that both HIF-2 and HIF-3 also contributes to the reprogramming of tumor cell metabolism
significantly impact neoplastic diseases. 9-12 from a state of oxidative phosphorylation to aerobic

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