Research ArticleCancer Metabolism

Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT

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Sci. Signal.  19 Dec 2017:
Vol. 10, Issue 510, eaao6604
DOI: 10.1126/scisignal.aao6604

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Understanding the causes of methionine dependency

Cells can use the same precursor to produce either methionine or cysteine, but can free up cysteine from cystine, an oxidized cysteine dimer with structural functions. Methionine dependency, or the inability to efficiently produce methionine, is a metabolic vulnerability that could be exploited to treat certain cancers. Examination of several breast cancer cell lines by Lien et al. revealed a correlation between methionine dependency, the presence of oncogenic mutations in PIK3CA, which encodes the lipid kinase PI3Kα, and decreased expression of SLC7A11, which encodes the cystine transporter xCT. Oncogenic PI3Kα mutants not only transcriptionally suppressed SLC7A11 expression but also inhibited the activity of xCT through AKT-mediated phosphorylation. These results highlight how mutations in the PI3K pathway result in the metabolic reprogramming of cancer cells.


The precursor homocysteine is metabolized either through the methionine cycle to produce methionine or through the transsulfuration pathway to synthesize cysteine. Alternatively, cysteine can be obtained through uptake of its oxidized form, cystine. Many cancer cells exhibit methionine dependency such that their proliferation is impaired in growth media in which methionine is replaced by homocysteine. We showed that oncogenic PIK3CA and decreased expression of SLC7A11, a gene that encodes a cystine transporter also known as xCT, correlated with increased methionine dependency in breast cancer cells. Oncogenic PIK3CA was sufficient to confer methionine dependency to mammary epithelial cells, partly by decreasing cystine uptake through the transcriptional and posttranslational inhibition of xCT. Manipulation of xCT activity altered the proliferation of breast cancer cells in methionine-deficient, homocysteine-containing media, suggesting that it functionally contributed to methionine dependency. We propose that concurrent with decreased cystine uptake through xCT, PIK3CA mutant cells use homocysteine through the transsulfuration pathway to synthesize cysteine. Consequently, less homocysteine is available to produce methionine, contributing to methionine dependency. These results indicate that oncogenic PIK3CA alters methionine and cysteine utilization, partly by inhibiting xCT to contribute to the methionine dependency phenotype in breast cancer cells.

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