Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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Oxygen-independent Regulation of HIF-1: Novel Involvement of PI3K/ AKT/mTOR Pathway in Cancer

Author(s): Faton Agani, Bing-Hua Jiang.

Abstract:

Studies on erythropoietin regulation led to discovery of hypoxia-inducible factor 1 (HIF-1), a transcription factor which is central component of oxygen sensing mechanism in mammalian cells. The number of HIF-1 and hypoxiaregulated target genes has grown exponentially and includes genes that encode proteins with roles in erythropoiesis, angiogenesis, glycolytic pathway, glucose transport, metastasis, and cell survival. Thus, HIF-1 claimed the role of the master that orchestrates cellular responses to oxygen deprivation. In addition, HIF-1 is also activated or influenced through oxygen-independent mechanisms via growth factors, deregulated oncogenes, and/or tumor suppressors. Whereas HIF prolyl hydroxylases (PHDs) regulate HIF-1 (and subsequently identified HIF-2) during hypoxia, the PI3K, AKT and MAPK pathways mediate primarily non-hypoxic HIF regulation. Here we will focus primarily on pathways that lead to HIF activation via PI3K/AKT, and mTOR/p70S6K1. In addition, recent studies have revealed novel factors and mechanisms that regulate oxygen-independent HIF-1α and HIF-2α degradation. HIFs play important roles in many processes in health and disease. Consequently, HIFs and pathways (PI3K/AKT and mTOR/p70S6K1) that lead to normoxic HIF activation are considered potential therapeutic targets in these pathologies.

Keywords: AKT, growth factors, HIF-1, hypoxia, MAPK, oncogenes, PI3K, tumor suppressors

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Article Details

VOLUME: 13
ISSUE: 3
Year: 2013
Page: [245 - 251]
Pages: 7
DOI: 10.2174/1568009611313030003
Price: $58