HIF2α Acts as an mTORC1 Activator through the Amino Acid Carrier SLC7A5

Abstract

The mammalian target of rapamycin (mTOR) pathway, which is essential for cell proliferation, is repressed in certain cell types in hypoxia. However, hypoxia-inducible factor 2α (HIF2α) can act as a proliferation-promoting factor in some biological settings. This paradoxical situation led us to study whether HIF2α has a specific effect on mTORC1 regulation. Here we show that activation of the HIF2α pathway increases mTORC1 activity by upregulating expression of the amino acid carrier SLC7A5. At the molecular level we also show that HIF2α binds to the Slc7a5 proximal promoter. Our findings identify a link between the oxygen-sensing HIF2α pathway and mTORC1 regulation, revealing the molecular basis of the tumor-promoting properties of HIF2α in von Hippel-Lindau-deficient cells. We also describe relevant physiological scenarios, including those that occur in liver and lung tissue, wherein HIF2α or low-oxygen tension drive mTORC1 activity and SLC7A5 expression.

Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth

“…This nutritional demand imposes a constant stress in tumors growing in hostile, acidic, and low nourished microenvironments (16,17). Thus, high expression and activity of LAT1, regulated by HIF2 as reported in lung tissues and kidney cancers, is implicated in the ability to sustain growth despite the challenges faced in the microenvironment (18). Numerous clinical studies have shown that the CD98/LAT1 complex is overexpressed and is a negative prognostic factor in different types of cancers, including prostate (19), non-small cell lung cancer (20), gliomas (21), and renal cell carcinomas (18,22).…”

Differential contribution of key metabolic substrates and cellular oxygen in HIF signalling

“…In anoxic cells (at least at 2 h time po int), Akt phosphorylation is strongly linked to Glc availability. Interestingly, HIF-2 can also activate TORC1 and increase cell proliferation under hypoxia by up-regulating expression of the amino acid carrier SLC7A5 [69].…”

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

“…SLC7A5 is highly expressed in most cancers (8), raising the possibility that the transporter functions in the maintenance of amino acid nutrition in cancer cells. Recent studies have demonstrated that the hypoxia-inducible factor HIF2a upregulates SLC7A5 (9). Because hypoxia plays a critical role in cancer growth and progression, the control of SLC7A5 expression by HIF2a offers a molecular mechanism for the high expression of this transporter in cancer.…”