谷氨酰胺是人體含量最豐富的非必需氨基酸,，也是癌細(xì)胞的主要營養(yǎng)來源,。既往研究發(fā)現(xiàn)，乳腺癌（尤其三陰性乳腺癌）細(xì)胞依靠谷氨酰胺獲得生存和增殖所需能量,。雖然細(xì)胞內(nèi)谷氨酰胺信號(hào)通路的作用已被深入研究,，但是關(guān)于乳腺癌谷氨酰胺轉(zhuǎn)運(yùn)蛋白研究極少。

　　2020年10月8日,，英國癌癥研究基金會(huì)《英國癌癥雜志》在線發(fā)表英國牛津大學(xué),、諾丁漢大學(xué)、倫敦大學(xué)癌癥研究院的研究報(bào)告,，探討了不同谷氨酰胺轉(zhuǎn)運(yùn)蛋白對(duì)不同乳腺癌細(xì)胞的影響,。

　　該研究首先分析了5種鈉偶聯(lián)中性氨基酸轉(zhuǎn)運(yùn)蛋白（SLC1A4、SLC1A5,、SLC7A5,、SLC38A1、SLC38A2）在谷氨酰胺缺乏或藥物刺激下對(duì)6種乳腺癌細(xì)胞（激素受體陽性MCF7,、激素受體陽性T47D,、HER2陽性SKBR3、三陰性HCC1806,、三陰性MDA-MB-231,、三陰性MDA-MB-468）的作用和分布。隨后,，敲低谷氨酰胺轉(zhuǎn)運(yùn)蛋白編碼基因表達(dá),，分析對(duì)谷氨酰胺敏感細(xì)胞的影響。最后,，通過免疫組織化學(xué)確定谷氨酰胺轉(zhuǎn)運(yùn)蛋白表達(dá)水平對(duì)于大樣本乳腺癌患者的預(yù)后價(jià)值,。

　　結(jié)果,，SLC38A2（又稱SNAT2）被確定為高表達(dá)于6種乳腺癌細(xì)胞的氨基酸轉(zhuǎn)運(yùn)蛋白,。通過自噬作用，SLC38A2可被溶酶體降解,。對(duì)于谷氨酰胺敏感細(xì)胞,，敲低SLC38A2編碼基因表達(dá)可減少谷氨酰胺攝入、誘發(fā)自噬作用,、引起氧自由基產(chǎn)生,、抑制乳腺癌細(xì)胞生長。

　　142例SLC38A2高表達(dá)與1338例SLC38A2低表達(dá)乳腺癌患者相比,，乳腺癌相關(guān)生存顯著較差（P=0.004）,；其中，33例SLC38A2高表達(dá)與75例SLC38A2低表達(dá)三陰性乳腺癌患者相比，乳腺癌相關(guān)生存顯著較差（P=0.02）,。

　　因此,，該研究結(jié)果表明，SLC38A2高表達(dá)可促進(jìn)乳腺癌（尤其三陰性乳腺癌）細(xì)胞對(duì)谷氨酰胺的依賴性和抗氧化應(yīng)激,，而且患者生存結(jié)局較差,，SLC38A2有望成為抑制谷氨酰胺依賴性乳腺癌（尤其三陰性乳腺癌）生長的新靶點(diǎn)。

Br J Cancer. 2020 Oct 8. Online ahead of print.

Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer.

Morotti M, Zois CE, El-Ansari R, Craze ML, Rakha EA, Fan SJ, Valli A, Haider S, Goberdhan DCI, Green AR, Harris AL.

University of Oxford, Oxford, UK; University of Nottingham, Nottingham, UK; The Institute of Cancer Research, London, UK.

BACKGROUND: Glutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and particularly triple-receptor negative breast cancer (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. Despite intense research on the role of the intracellular Gln pathway, few reports have focussed on Gln transporters in breast cancer and TNBC.

METHODS: The role and localisation of the Gln transporter SLC38A2/SNAT2 in response to Gln deprivation or pharmacological stresses was examined in a panel of breast cancer cell lines. Subsequently, the effect of SLC38A2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SLC38A2 in a cohort of breast cancer was determined by immunohistochemistry.

RESULTS: SLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SLC38A2. SLC38A2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of Gln-sensitive cell lines. High expression of SLC38A2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p=0.004), particularly in TNBC (p=0.02).

CONCLUSIONS: These results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines.

PMID: 33028955

DOI: 10.1038/s41416-020-01113-y