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Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)

胱氨酸/谷氨酸逆向轉(zhuǎn)運(yùn)蛋白 xCT 的過度表達(dá)與高克隆性膠質(zhì)母細(xì)胞瘤干細(xì)胞樣細(xì)胞 (GSC) 中的營(yíng)養(yǎng)靈活性和 ZEB1 表達(dá)相關(guān)

Glioblastoma (GBM) is the most aggressive form of glioma (WHO grade IV), and mounting evidence suggests that glioblastoma stem-like cells (GSCs) play an important role in tumor growth and response to therapy. In the current study, we sought to understand the metabolic dependencies of GSCs using high-resolution proton magnetic resonance spectroscopy (1H-NMR). In a defined experimental setting, we stratified in vitro GSC models into two subtypes (Gln/GluHigh, Gln/GluLow) and used diverse molecular approaches to perform comprehensive analyses in GSC neurosphere cultures and primary GBM samples.

膠質(zhì)母細(xì)胞瘤 (GBM) 是最具侵襲性的膠質(zhì)瘤形式（WHO IV 級(jí)），越來越多的證據(jù)表明，膠質(zhì)母細(xì)胞瘤干細(xì)胞樣細(xì)胞 (GSC) 在腫瘤生長(zhǎng)和治療反應(yīng)中發(fā)揮著重要作用。在當(dāng)前的研究中，我們?cè)噲D使用高分辨率質(zhì)子磁共振波譜 ( 1 H-NMR)來了解 GSC 的代謝依賴性。在定義的實(shí)驗(yàn)環(huán)境中，我們將體外 GSC 模型分為兩個(gè)亞型（Gln/Glu高、Gln/Glu低），并使用不同的分子方法對(duì) GSC 神經(jīng)球培養(yǎng)物和原代 GBM 樣本進(jìn)行綜合分析。

三角細(xì)胞搖瓶

Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.

10層細(xì)胞工廠

癌癥干細(xì)胞樣細(xì)胞介導(dǎo)腫瘤的發(fā)生、進(jìn)展和治療抵抗；然而，它們的識(shí)別和選擇性根除仍然具有挑戰(zhàn)性。在此，我們使用高分辨率質(zhì)子核磁共振 ( 1 H-NMR) 光譜分析了膠質(zhì)母細(xì)胞瘤干細(xì)胞樣細(xì)胞 (GSC) 的代謝依賴性。我們主要根據(jù)谷氨酰胺與谷氨酸 (Gln/Glu) 的相對(duì)量將我們的體外 GSC 模型分為兩個(gè)亞型。發(fā)現(xiàn)Gln/Glu高GSCs 對(duì)谷氨酰胺剝奪具有抵抗力，而 Gln/Glu低GSCs 以顯著降低的體外克隆形成和受損的細(xì)胞生長(zhǎng)作出反應(yīng)。饑餓抗性似乎是由谷氨酸/胱氨酸逆向轉(zhuǎn)運(yùn)蛋白 SLC7A11/xCT 的表達(dá)增加和活性氧 (ROS) 的有效細(xì)胞清除介導(dǎo)的。此外，我們能夠?qū)?xCT 依賴性饑餓抗性和高 Gln/Glu 比率與體外克隆形成直接相關(guān)聯(lián)，因?yàn)榫哂泄切螒B(tài)發(fā)生蛋白 4（BMP4）的 GSC 的靶向分化損害了 xCT 表達(dá)，降低了 Gln/Glu 比率，并恢復(fù)了對(duì)谷氨酰胺饑餓的敏感性。此外，在分化的 GSC 中觀察到癌代謝物乳酸 (Lac)、磷酸膽堿 (PC)、總膽堿 (tCho)、肌醇 (Myo-I) 和甘氨酸 (Gly) 的水平顯著降低。此外，我們發(fā)現(xiàn)高 Gln/Glu 比率與鋅指 E-box 結(jié)合同源框 1 (ZEB1) 和 xCT 在原發(fā)性 GBM 腫瘤組織中的表達(dá)增加之間存在很強(qiáng)的關(guān)聯(lián)。我們的分析表明，xCT 的抑制代表了膠質(zhì)母細(xì)胞瘤的潛在治療靶點(diǎn)；因此，我們可以進(jìn)一步擴(kuò)展其在 GSC 生物學(xué)和應(yīng)激反應(yīng)中的重要性。我們還建議監(jiān)測(cè)細(xì)胞內(nèi) Gln/Glu 比率可用于預(yù)測(cè)營(yíng)養(yǎng)脅迫抗性。

關(guān)鍵詞：glioblastoma;cancerstemcells; NMRspectroscopy; glutamine; metabolism; xCT; ZEB1; oncometabolites； 膠質(zhì)母細(xì)胞瘤；癌癥干細(xì)胞；核磁共振光譜；谷氨酰胺；新陳代謝；xCT ; ZEB1 ; 癌代謝物

來源：MDPI https://www.mdpi.com/2072-6694/13/23/6001/htm