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Targeting HIF-1 for cancer therapy

Key Points

  • Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric protein that consists of two proteins — HIF-1α and HIF-1β. HIF-1 activates the transcription of many genes that code for proteins that are involved in angiogenesis, glucose metabolism, cell proliferation/survival and invasion/metastasis.

  • HIF-1α protein synthesis is regulated by activation of the phosphatidylinositol 3-kinase (PI3K) and ERK mitogen-activated protein kinase (MAPK) pathways. These pathways can be activated by signalling via receptor tyrosine kinases, non-receptor tyrosine kinases or G-protein-coupled receptors.

  • HIF-1α protein degradation is regulated by O2-dependent prolyl hydroxylation, which targets the protein for ubiquitylation by E3 ubiquitin-protein ligases. These ligases contain the von Hippel–Lindau tumour-suppressor protein (VHL), which binds specifically to hydroxylated HIF-1α. Ubiquitylated HIF-1α is rapidly degraded by the proteasome.

  • HIF-1α is overexpressed in human cancers as a result of intratumoral hypoxia as well as genetic alterations, such as gain-of-function mutations in oncogenes (for example, ERBB2) and loss-of-function mutations in tumour-suppressor genes (for example, VHL and PTEN). HIF-1α overexpression is associated with treatment failure and increased mortality.

  • In xenograft assays, manipulation of HIF-1 activity by genetic or pharmacological means has marked effects on tumour growth because of effects on angiogenesis, glucose metabolism and/or cell survival.

  • Screens are underway to identify small-molecule inhibitors of HIF-1 and to test their efficacy as anticancer agents. These drugs might represent an important component of novel combination therapies that are designed to target signalling molecules in cancer cells.

Abstract

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1α overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

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Figure 1: Regulation of HIF-1α protein synthesis.
Figure 2: O2-dependent regulation of HIF-1 activity.
Figure 3: Genes that are transcriptionally activated by HIF-1.
Figure 4: Mechanisms and consequences of HIF-1 activity in cancer cells.
Figure 5: HIF-1 target genes that encode invasion factors.
Figure 6: Involvement of HIF-1 in autocrine growth-factor stimulation of cancer cells.

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DATABASES

Cancer.gov

brain cancer

breast cancer

cervical cancer

head and neck cancer

oesophageal cancer

oropharyngeal cancer

ovarian cancer

pancreatic cancer

prostate cancer

uterus

LocusLink

AKT

ARD1

BCL2

BNIP3

CBP

FIH-1

GLUT1

HIF-1α

HIF-2α

HIF-3α

HSP90

IGF2

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p53

p300

PDGF-β

PI3K

RAF

TGF-α

VEGF

VHL

OMIM

glioblastoma multiforme

Glossary

GLYCOLYTIC METABOLISM

Two molecules of ATP and NADH are generated by the conversion of one molecule of glucose to two molecules of pyruvate. The NADH is then used to reduce pyruvate to lactate.

OXIDATIVE METABOLISM

Glucose is converted to pyruvate, which is transported to the mitochondria, converted to acetyl coenzyme A and oxidized to CO2 in the citric-acid cycle. The NADH and FADH2 generated in this process provide electrons to respiratory cytochromes and, ultimately, to O2 in the inner mitochondrial membrane, generating ATP. The complete oxidation of one molecule of glucose results in the production of 36 molecules of ATP.

SV40 T-ANTIGEN

Large T-antigen — produced in the early stage following infection of cells with simian virus 40 —promotes transformation by binding to and inactivating the host p53 and RB (retinoblastoma gene product) proteins.

NCI DIVERSITY SET

A group of approximately 2,000 compounds that is representative of the complete chemical repository of the National Cancer Institute's Developmental Therapeutics Program.

TOPOISOMERASE I INHIBITORS

Drugs that inhibit an enzyme that relaxes supercoiled DNA by introducing a transient single-strand break.

PSEUDOPALISADING CELLS

Rows of viable cells surrounding areas of necrosis that are a histopathological characteristic of glioblastoma multiforme.

ORTHOTOPIC TRANSPLANTATION

The introduction of foreign tumour cells into another species at the site from which they were derived. For example, injection of human breast cancer cells into the mouse mammary fat pad.

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Semenza, G. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721–732 (2003). https://doi.org/10.1038/nrc1187

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