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Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT
Science Signaling ( IF 7.3 ) Pub Date : 2017-12-19 , DOI: 10.1126/scisignal.aao6604
Evan C. Lien 1 , Laura Ghisolfi 1 , Renee C. Geck 1 , John M. Asara 2, 3 , Alex Toker 1, 2, 3, 4
Affiliation  

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.



中文翻译:

致癌性PI3K通过胱氨酸-谷氨酸逆转运蛋白xCT促进乳腺癌细胞中蛋氨酸的依赖性

前体高半胱氨酸通过蛋氨酸循环代谢生成蛋氨酸,或通过转硫途径代谢以合成半胱氨酸。或者,可以通过摄取其氧化形式的胱氨酸来获得半胱氨酸。许多癌细胞表现出蛋氨酸依赖性,因此在其中蛋氨酸被高半胱氨酸替代的生长培养基中其增殖受到损害。我们显示,致癌的PIK3CASLC7A11(一种编码胱氨酸转运蛋白,也称为xCT)的基因表达降低,与乳腺癌细胞中蛋氨酸的依赖性增加有关。致癌PIK3CA足以使甲硫氨酸对乳腺上皮细胞具有依赖性,部分原因是通过xCT的转录和翻译后抑制作用降低了胱氨酸的摄取。xCT活性的操纵改变了蛋氨酸缺乏,含高半胱氨酸的培养基中乳腺癌细胞的增殖,表明它在功能上有助于蛋氨酸的依赖性。我们建议,与通过xCT减少的胱氨酸摄取同时,PIK3CA突变细胞通过转硫途径使用高半胱氨酸来合成半胱氨酸。因此,较少的同型半胱氨酸可用于生产蛋氨酸,从而导致蛋氨酸的依赖性。这些结果表明,致癌的PIK3CA 改变蛋氨酸和半胱氨酸的利用率,部分是通过抑制xCT来促进乳腺癌细胞中蛋氨酸的依赖表型。

更新日期:2017-12-20
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