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Sci Signal. 2017 Dec 19;10(510). pii: eaao6604. doi: 10.1126/scisignal.aao6604.

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

Author information

1
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
2
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston 02215 MA, USA.
3
Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
4
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. atoker@bidmc.harvard.edu.
5
Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.

Abstract

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.

PMID:
29259101
PMCID:
PMC5808948
DOI:
10.1126/scisignal.aao6604
[Indexed for MEDLINE]
Free PMC Article

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