HIF1a regulates mTOR signaling and viability of prostate cancer stem cells

Abstract

Tumor-initiating subpopulations of cancer cells, also known as cancer stem cells (CSC), were recently identified and characterized in prostate cancer. A well-characterized murine model of prostate cancer was used to investigate the regulation of hypoxia-inducible factor 1a (HIF1A/HIF1a) in CSCs and a basal stem cell subpopulation (Lin-/Sca-1+/CD49f+) was identified, in primary prostate tumors of mice, with elevatedHIF1a expression. To further analyze the consequences of hypoxic upregulation on stem cell proliferation and HIF1a signaling, CSC subpopulations from murine TRAMP-C1cells (Sca-1+/CD49f+)aswellas fromahumanprostate cancer cell line (CD44+/CD49f+) were isolated and characterized. HIF1a levels and HIF target gene expression were elevated in hypoxic CSC-like cells, and upregulation of AKT occurred through a mechanisminvolving anmTOR/S6K/IRS-1 feedback loop. Interestingly, resistance of prostate CSCs to selective mTOR inhibitors was observed because of HIF1a upregulation. Thus, prostate CSCs show a hypoxic deactivation of a feedback inhibition of AKT signaling through IRS-1. In light of these results, we propose that deregulation of the PI3K/AKT/mTOR pathway through HIF1a is critical for CSC quiescence and maintenance by attenuating CSC metabolism and growth via mTORand promoting survival by AKT signaling. We also propose that prostate CSCs can exhibit primary drug resistance to selective mTOR inhibitors.