Targeting HIF-1 for cancer therapy

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Abstract
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.