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Abstract
Hypoxia is one of the intrinsic features of solid tumors and it is
always associated with aggressive phenotypes, including resistance to
radiation and chemotherapy, metastasis, and poor patient prognosis. Hypoxia
manifests these unfavorable effects through activation of a family of
transcription factors, Hypoxia- inducible factors (HIFs) play a pivotal role
in the adaptation of tumor cells to hypoxic and nutrient-deprived conditions
by upregulating the transcription of several pro-oncogenic genes. Several
advanced human cancers share HIFs activation as a final common pathway. This review
highlights the role and regulation of the HIF-1/2 in
cancers and alludes on the biological complexity and redundancy of HIF-1/2
regulation. Moreover, this review summarizes recent insights into the
therapeutic approaches targeting the HIF-1/2 pathway. More studies are needed to unravel
the extensive complexity of HIFs
regulation and to develop more precise anticancer treatments. Inclusion of
HIF-1/2 inhibitors to the current chemotherapy regimens has been proven
advantageous in numerous reported preclinical studies. The combination
therapy ideally should be personalized based on the type of mutations
involved in the specific cancers and it might be better to include two drugs
that inhibit HIF-1/2 activity by synergistic molecular mechanisms.
Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.
During hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) is required for induction of a variety of genes including erythropoietin and vascular endothelial growth factor. Hypoxia increases mitochondrial reactive oxygen species (ROS) generation at Complex III, which causes accumulation of HIF-1alpha protein responsible for initiating expression of a luciferase reporter construct under the control of a hypoxic response element. This response is lost in cells depleted of mitochondrial DNA (rho(0) cells). Overexpression of catalase abolishes hypoxic response element-luciferase expression during hypoxia. Exogenous H(2)O(2) stabilizes HIF-1alpha protein during normoxia and activates luciferase expression in wild-type and rho(0) cells. Isolated mitochondria increase ROS generation during hypoxia, as does the bacterium Paracoccus denitrificans. These findings reveal that mitochondria-derived ROS are both required and sufficient to initiate HIF-1alpha stabilization during hypoxia.
Mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of HIF is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF. We identified a conserved family of HIF prolyl hydoxylase (HPH) enzymes that appear to be responsible for this posttranslational modification. In cultured mammalian cells, inappropriate accumulation of HIF caused by forced expression of the HIF-1alpha subunit under normoxic conditions was attenuated by coexpression of HPH. Suppression of HPH in cultured Drosophila melanogaster cells by RNA interference resulted in elevated expression of a hypoxia-inducible gene (LDH, encoding lactate dehydrogenase) under normoxic conditions. These findings indicate that HPH is an essential component of the pathway through which cells sense oxygen.