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

Here, we described a novel regulatory feedback loop in which hypoxia induces integrin-linked kinase (ILK) expression through a HIF-1 alpha-dependent mechanism and ILK, in turn, stimulates HIF-1 alpha expression through cell type-and cell context-dependent pathways. HIF-1 alpha increased ILK via transcriptional activation. ILK increased HIF-1 alpha levels by promoting mTOR-mediated translation in PC-3 and MCF-7 cells, and by blocking GSK3 beta-mediated degradation in LNCaP cells, consistent with the cell line-/cellular context-specific functions of ILK as a Ser473-Akt kinase. We show that ILK can account for the effects of hypoxia on Akt, mTOR, and GSK3 beta phosphorylation. Also, ILK can de-repress HIF-1 alpha signaling through the YB-1-mediated inhibition of Foxo3 alpha expression. In concert with HIF-1 alpha, these downstream effectors promote epithelial-mesenchymal transition (EMT) through modulation of Snail and Zeb1. Thus, the ILK-HIF-1 alpha regulatory loop could underlie the maintenance of high HIF-1 alpha expression levels and the promotion of EMT under hypoxic conditions. Finally, we show that the small-molecule ILK inhibitor T315 can disrupt this regulatory loop in vivo and suppress xenograft tumor growth, thereby providing proof-of-concept that targeting ILK represents an effective strategy to block HIF-1 alpha expression and aggressive phenotype in cancer cells.