Abstract
The Hypoxia Inducible factor (HIF) pathway is known to be constitutionally active in various cancers and is the dominant pathway in some cancers such as VHL mutant clear cell Renal cell carcinoma. HIF-1α and HIF-2α overexpression is known to be important for tumor cell proliferation, maintenance of stemness and angiogenesis. There has been growing interest in therapeutic strategies targeting the HIF pathway over the last decade. We review in this section the role of hypoxia inducible factor pathway in carcinogenesis, its crosstalk with other pathways and potential cancer therapeutic strategies targeting the HIF pathway, its upstream regulators and downstream signaling.
Highlights
Introduction and Brief Overview of theHypoxia Inducible factor (HIF) PathwayUnder normoxic conditions, prolyl hydroxylases in the presence of Fe2+ and 2-oxoglutarate (2-OG), hydroxylate the proline residues in the Oxygen Degradation Domain of the α subunit of HIF-α
Inactivating mutations of tumor suppressor PTEN leads to enhanced Phosphatidylinositol 3-Kinase (PI3K) levels, thereby augmenting the downstream HIF pathway
Under hypoxic conditions NFκB leads to increased production of RAGE which binds to KRAS thereby effecting the downstream signaling via RAF-MEK-ERK and PI3K-AKT leading to increased translation and stabilization of HIF-1α
Summary
Prolyl hydroxylases in the presence of Fe2+ and 2-oxoglutarate (2-OG), hydroxylate the proline residues in the Oxygen Degradation Domain of the α subunit of HIF-α. The hydroxylated HIF-α binds to VHL and undergoes polyubiquitination and proteasomal degradation. (2015) The Regulation and Interactions of the Hypoxia Inducible Factor Pathway in Carcinogenesis and Potential Cancer Therapeutic Strategies. The pattern of transcription mediates cellular responses to hypoxia and can up-regulate the expression of multiple genes that contribute to cancer progression through survival, angiogenesis, invasion and metastasis. It is not surprising that there has been growing interest in targeting the HIF pathway as a potential cancer therapeutic strategy
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