HIF1α Regulates mTOR Signaling and Viability of Prostate Cancer Stem Cells

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/HIF1 alpha) in CSCs and a basal stem cell subpopulation (Lin(-)/Sca-1(+)/CD49f(+)) was identified, in primary prostate tumors of mice, with elevated HIF1a expression. To further analyze the consequences of hypoxic upregulation on stem cell proliferation and HIF1 alpha signaling, CSC subpopulations from murine TRAMP-C1 cells (Sca-1(+)/CD49f(+)) as well as from a human prostate cancer cell line (CD44(+)/CD49f(+)) were isolated and characterized. HIF1 alpha levels and HIF target gene expression were elevated in hypoxic CSC-like cells, and upregulation of AKT occurred through a mechanism involving an mTOR/S6K/IRS-1 feedback loop. Interestingly, resistance of prostate CSCs to selective mTOR inhibitors was observed because of HIF1 alpha 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 HIF1 alpha is critical for CSC quiescence and maintenance by attenuating CSC metabolism and growth via mTOR and promoting survival by AKT signaling. We also propose that prostate CSCs can exhibit primary drug resistance to selective mTOR inhibitors.