A novel HIF-1α-integrin-linked kinase regulatory loop that facilitates hypoxia-induced HIF-1α expression and epithelial-mesenchymal transition in cancer cells

摘要: Here, we described a novel regulatory feedback loop in which hypoxia induces integrin-linked kinase (ILK) expression through HIF-1α-dependent mechanism and ILK, turn, stimulates HIF-1α cell type- context-dependent pathways. increased ILK via transcriptional activation. levels by promoting mTOR-mediated translation PC-3 MCF-7 cells, blocking GSK3β-mediated degradation LNCaP consistent with the line-/cellular context-specific functions of as Ser473-Akt kinase. We show that can account for effects on Akt, mTOR, GSK3β phosphorylation. Also, de-repress signaling YB-1-mediated inhibition Foxo3a expression. In concert HIF-1α, these downstream effectors promote epithelial-mesenchymal transition (EMT) modulation Snail Zeb1. Thus, ILK-HIF-1α could underlie maintenance high promotion EMT under hypoxic conditions. Finally, small-molecule inhibitor T315 disrupt this vivo suppress xenograft tumor growth, thereby providing proof-of-concept targeting represents an effective strategy to block aggressive phenotype cancer cells.