Title:Oxygen-independent Regulation of HIF-1: Novel Involvement of PI3K/ AKT/mTOR Pathway in Cancer
Volume: 13
Issue: 3
Author(s): Faton Agani and Bing-Hua Jiang
Affiliation:
Keywords:
AKT, growth factors, HIF-1, hypoxia, MAPK, oncogenes, PI3K, tumor suppressors
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.
