mTORC2 Regulates the Cystine–Glutamate Antiporter xCT

Amino acid metabolism is often dysregulated in cancer, but the underlying molecular mechanisms have not been fully elucidated. The cystine–glutamate antiporter xCT (encoded by SLC7A11) is a transmembrane protein that interacts with CD98 to form the system x_c⁻ transporter, which takes up cystine in exchange for glutamate, and xCT is highly expressed in multiple tumor types. To uncover potential mechanisms of xCT regulation, Gu and colleagues performed an unbiased mass spectrometry screen to identify xCT binding partners. In glioblastoma, lung cancer, and triple-negative breast cancer cell lines, xCT was associated with the mTORC2 complex components mTOR and Rictor, but not mTORC1 complex–specific components, suggesting that mTORC2 may regulate xCT activity. Indeed, in response to EGFR signaling, mTORC2 phosphorylated xCT at serine 26 in the cytosolic N terminus, resulting in inhibition of xCT activity and reduced glutamate secretion. Conversely, in cancer cell lines with high levels of xCT and mTORC2 activity, mTORC2 inhibition, via Rictor depletion or treatment with the mTOR kinase inhibitor Torin1, increased glutamate secretion and cystine uptake, suggesting enhanced xCT activity. Further, Torin1 treatment increased the incorporation of cystine into glutathione, which plays a critical role in buffering reactive oxygen species in nutrient-depleted conditions and in anabolic reactions when nutrients are available. Thus, reducing glutathione levels via xCT knockdown and Torin1 treatment promoted glioblastoma cell death. Collectively, these findings reveal a mechanism by which mTORC2 regulates cystine uptake and glutathione metabolism via xCT phosphorylation, thereby linking growth factor signaling to amino acid metabolism in cancer.

Gu Y, Albuquerque CP, Braas D, Zhang W, Villa GR, Bi J, et al. mTORC2 regulates amino acid metabolism in cancer by phosphorylation of the cystine-glutamate antiporter xCT. Mol Cell 2017;67:128–38.e7.

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