Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT.
Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT.
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DOI：
10.1126/scisignal.aao6604
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发表时间：
2017-12-19
影响因子：
7.3
通讯作者：
Toker A
中科院分区：
文献类型：
--
作者：
Lien EC;Ghisolfi L;Geck RC;Asara JM;Toker A
前体同型半胱氨酸通过蛋氨酸循环代谢产生蛋氨酸，或者通过硫化途径合成半胱氨酸。或者，半胱氨酸可以通过摄取其氧化形式半胱氨酸来获得。许多癌细胞表现出对蛋氨酸的依赖，以至于在蛋氨酸被同型半胱氨酸取代的生长介质中，它们的增殖受到损害。在这里，我们发现致癌的PIK3CA和SLC7A11的表达减少，SLC7A11是一种编码胱氨酸转运体的基因，也被称为XCT，与乳腺癌细胞对蛋氨酸的依赖性增加相关。致癌的PIK3CA足以赋予乳腺上皮细胞蛋氨酸依赖，部分原因是通过XCT的转录和翻译后抑制减少了胱氨酸的摄取。XCT活性的操纵改变了乳腺癌细胞在蛋氨酸缺乏、含同型半胱氨酸的培养液中的增殖，表明它在功能上促进了蛋氨酸依赖。我们认为，在通过XCT减少半胱氨酸摄取的同时，PIK3CA突变细胞通过跨硫途径使用同型半胱氨酸来合成半胱氨酸。因此，可用于生产蛋氨酸的同型半胱氨酸较少，从而导致蛋氨酸依赖。这些结果表明，致癌的PIK3CA改变了蛋氨酸和半胱氨酸的利用，部分是通过抑制XCT，从而促进了乳腺癌细胞的蛋氨酸依赖表型。
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. Here, 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, in part 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, in part by inhibiting xCT, to contribute to the methionine dependency phenotype in breast cancer cells.
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DOI：
10.1073/pnas.71.4.1133
发表时间：
1974-01-01
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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影响因子：
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DOI：
10.1126/science.1236566
发表时间：
2013-07-26
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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DOI：
10.1126/science.1199498
发表时间：
2011-06-10
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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通讯作者：
Sabatini DM