SLC7A11：SLC家族氨基酸轉(zhuǎn)運(yùn)蛋白，抗鐵死亡！腫瘤耐藥新方向！
日期：2022-10-13 13:46:09
近期，Cell 雜志推出重磅“鐵死亡”綜述，紀(jì)念鐵死亡十周年 [1]！該文章主要介紹了鐵死亡的關(guān)鍵調(diào)控因子，以及未來(lái)利用鐵死亡來(lái)促進(jìn)治療方面的前景。SLC7A11作為鐵死亡的最關(guān)鍵的上游調(diào)節(jié)因子之一，近年來(lái)，大量文獻(xiàn)早已揭示SLC7A11驅(qū)動(dòng)鐵死亡抗性，在腫瘤等疾病中發(fā)揮調(diào)控作用。SLC7A11不僅是鐵死亡的有效靶標(biāo)，在多種腫瘤耐藥的治療中，SLC7A11也扮演重要的角色，包括肺腺癌、胃癌、結(jié)直腸癌、膠質(zhì)瘤等等。到目前為止，研究學(xué)者已經(jīng)探索多種抗癌方法，然而，有效治療的一個(gè)主要障礙是對(duì)抗癌治療的適應(yīng)性耐藥性。SLC7A11對(duì)于這一障礙所帶來(lái)的影響，有望提供走出困境的替代方案。那么，SLC7A11是什么家族蛋白？SLC7A11在鐵死亡及腫瘤耐藥中的機(jī)制又如何？今天我們一起來(lái)了解一下。
1. 什么是溶質(zhì)轉(zhuǎn)運(yùn)蛋白SLC？
溶質(zhì)載體（Solute Carriers, SLC），即溶質(zhì)轉(zhuǎn)運(yùn)蛋白超家族是人類(lèi)細(xì)胞膜（含胞內(nèi)膜）上最重要的膜轉(zhuǎn)運(yùn)蛋白家族之一 [2]。目前已鑒定的人源SLC轉(zhuǎn)運(yùn)蛋白超家族系列包含52個(gè)亞家族，共400多個(gè)成員 [2, 3]。SLC轉(zhuǎn)運(yùn)蛋白超家族是僅次于G蛋白偶聯(lián)受體（GPCR）后的第二大膜蛋白家族 [4]。SLCs亞細(xì)胞分布廣泛，除可分布于細(xì)胞膜外，還可分布在細(xì)胞核膜、內(nèi)質(zhì)網(wǎng)、線粒體、溶酶體、高爾基體和過(guò)氧化物酶體等細(xì)胞器 [4, 5]。SLC作為典型的跨膜蛋白，介導(dǎo)各種營(yíng)養(yǎng)物質(zhì)和代謝產(chǎn)物的跨膜生物膜轉(zhuǎn)運(yùn)，包括金屬離子、無(wú)機(jī)離子、有機(jī)離子、氨基酸、脂質(zhì)、糖類(lèi)、神經(jīng)遞質(zhì)、核酸和藥物等 [6-8] （圖1）。
研究表明，SLCs蛋白表達(dá)異常或功能缺陷與多種疾病的發(fā)生發(fā)展密切相關(guān)，包括腫瘤、代謝性疾病、心血管疾病、免疫系統(tǒng)和神經(jīng)功能障礙等等，使得該家族蛋白的功能研究近年來(lái)備受關(guān)注 [7]。尤其在腫瘤中，SLC的成員作為氨基酸轉(zhuǎn)運(yùn)體的主要組成部分，腫瘤細(xì)胞對(duì)于氨基酸的大量攝取主要是通過(guò)各種過(guò)表達(dá)的氨基酸轉(zhuǎn)運(yùn)體實(shí)現(xiàn)的 [7-8]。因此，通過(guò)靶向SLC家族的氨基酸轉(zhuǎn)運(yùn)體，實(shí)現(xiàn)對(duì)腫瘤生長(zhǎng)的抑制成為一個(gè)有效的策略。
圖1. 溶質(zhì)轉(zhuǎn)運(yùn)體SLC介導(dǎo)的物質(zhì)轉(zhuǎn)運(yùn) [6-8]
2. 什么是SLC7A11？
溶質(zhì)載體家族成員SLC7A11（Solute Carrier Family 7 Member 11，又名xCT）是溶質(zhì)轉(zhuǎn)運(yùn)第7家族的第11個(gè)成員，屬于胱氨酸/谷氨酸逆向轉(zhuǎn)運(yùn)蛋白，主要參與氨基酸在質(zhì)膜上的轉(zhuǎn)運(yùn) [9, 10]。SLC7A11基因位于人染色體4q28-q32，具有14個(gè)外顯子，編碼氨基酸轉(zhuǎn)運(yùn)載體xCT，其蛋白由501個(gè)氨基酸組成，包括12個(gè)跨膜結(jié)構(gòu)域，其N(xiāo)端和C端均存在于細(xì)胞質(zhì)內(nèi) [9, 10, 11]（圖2）。SLC7A11作為輕鏈亞基，與重鏈亞基SLC3A2組成胱氨酸/谷氨酸反轉(zhuǎn)運(yùn)體(Xc-系統(tǒng))，但發(fā)揮主要轉(zhuǎn)運(yùn)功能活性的是SLC7A11 [9-12]。近幾年的國(guó)內(nèi)外研究表明，SLC7A11高表達(dá)于多種實(shí)體惡性腫瘤，如乳腺癌、胰腺癌、卵巢癌和膠質(zhì)瘤等等，且與惡性腫瘤的治療耐藥性有著密切的關(guān)系 [13-14]。目前，SLC7A11已經(jīng)成為抗癌治療的一個(gè)研究重點(diǎn)。
圖2. SLC7A11的結(jié)構(gòu) [11]
3. SLC7A11相關(guān)的調(diào)節(jié)機(jī)制
3.1 SLC7A11和Xc-系統(tǒng)
胱氨酸/谷氨酸轉(zhuǎn)運(yùn)體系統(tǒng)(cystine/glutamate transporter, Xc-系統(tǒng)）是氨基酸轉(zhuǎn)運(yùn)體家族中的重要亞型。Xc-系統(tǒng)由輕鏈SLC7A11和重鏈SLC3A2兩種蛋白質(zhì)組成 [10]。SLC3A2作為其伴侶蛋白，用于維持SLC7A11蛋白的穩(wěn)定性并調(diào)節(jié)SLC7A11向質(zhì)膜的運(yùn)輸。輕鏈亞基SLC7A11作為Xc-系統(tǒng)的功能亞基，SLC7A11對(duì)胱氨酸和谷氨酸具有高度特異性，其作用是參與胱氨酸的胞外攝取和谷氨酸釋放，促進(jìn)谷胱甘肽（glutathione，r-glutamyl cysteingl+glycine，GSH)的合成，保護(hù)細(xì)胞免受氧化應(yīng)激的損傷，維持細(xì)胞氧化還原平衡，從而阻止細(xì)胞因脂質(zhì)過(guò)氧化而導(dǎo)致的細(xì)胞死亡 [9-12]。目前，對(duì)Xc-系統(tǒng)的研究主要集中于輕鏈亞基SLC7A11（圖3） [41]。
圖3. SLC7A11 在Xc-系統(tǒng)中發(fā)揮主要作用 [41]
3.2 SLC7A11與鐵死亡
SLC7A11是特異性的氨基酸轉(zhuǎn)運(yùn)蛋白，也是鐵死亡的關(guān)鍵調(diào)節(jié)蛋白（點(diǎn)擊可查看“鐵死亡”專(zhuān)題文章）。SLC7A11的下調(diào)可通過(guò)抑制半胱氨酸代謝通路，導(dǎo)致細(xì)胞內(nèi)胱氨酸水平降低和GSH生物合成耗竭，間接抑制GPX4的活性，進(jìn)而導(dǎo)致脂質(zhì)過(guò)氧化物堆積，最終誘導(dǎo)細(xì)胞發(fā)生鐵死亡（圖4） [15, 16]。此外，經(jīng)典的鐵死亡促進(jìn)劑Erastin，可靶向SLC7A11，誘導(dǎo)鐵死亡，逆轉(zhuǎn)結(jié)直腸癌耐藥 [17, 18]。研究人員發(fā)現(xiàn)，過(guò)表達(dá)SOCS2可促進(jìn)鐵死亡關(guān)鍵蛋白SLC7A11發(fā)生K48鏈型泛素化降解，調(diào)控肝癌中鐵死亡的發(fā)生 [19]。近期還有研究表明，活化后的腫瘤蛋白53（p53）可以結(jié)合到SLC7A11基因的啟動(dòng)子區(qū)，從而抑制了SLC7A11基因的轉(zhuǎn)錄活性，影響GSH的合成，可誘導(dǎo)發(fā)生鐵死亡 [20, 21]。
圖4. SLC7A11/GPX4通路在鐵死亡中的作用方式 [15, 16]
3.3 SLC7A11與腫瘤耐藥
腫瘤中SLC7A11介導(dǎo)的GSH水平升高，其過(guò)程參與化療藥物治療耐藥。例如，在膠質(zhì)瘤中，SLC7A11過(guò)表達(dá)，可增加膠質(zhì)瘤細(xì)胞對(duì)氧化應(yīng)激的抵抗力，降低對(duì)替莫唑胺（Temozolomide）的敏感性 [22, 23]。在黑色素瘤中，SLC7A11通過(guò)增加細(xì)胞內(nèi)GSH含量，使黑色素瘤對(duì)BRAF抑制劑產(chǎn)生耐藥性，而組蛋白去乙酰化酶抑制劑抑制SLC7A11能夠顯著誘導(dǎo)腫瘤消退 [25]。在大腸癌中，特異性SLC7A11抑制劑-柳氮磺吡啶（Sulfasalazine，SSZ），可有效增強(qiáng)順鉑（Cisplatin）在癌細(xì)胞內(nèi)的藥物含量和細(xì)胞毒性 [12]。在膀胱癌中，下調(diào)SLC7A11表達(dá)，耐藥細(xì)胞對(duì)cisplatin的敏感性明顯增加 [25]。三陰性乳腺癌患者中，SLC7A11、ATF4的表達(dá)遠(yuǎn)高于正常乳腺組織，eIF2α/ATF4軸上調(diào)SLC7A11的表達(dá)，促進(jìn)GSH合成，抑制活性氧自由基ROS的積累，而eIF2α去磷酸化使SLC7A11表達(dá)降低，caspase-3表達(dá)增加，誘導(dǎo)三陰性乳腺癌細(xì)胞凋亡，使得對(duì)順鉑和多柔比星（Doxorubicin）更加敏感，降低耐藥性 [26, 27]。因此，SLC7A11可能為治療多種耐藥相關(guān)腫瘤的治療靶點(diǎn)。
4. SLC7A11在腫瘤靶向治療中的作用
4.1 SLC7A11與神經(jīng)系統(tǒng)腫瘤
研究表明，SLC7A11可作為轉(zhuǎn)錄激活因子4（ATF4）的靶標(biāo)，在人膠質(zhì)母細(xì)胞瘤細(xì)胞U87和U251中，過(guò)表達(dá)ATF4通過(guò)增加SLC7A11的表達(dá)，抑制腫瘤細(xì)胞發(fā)生鐵死亡，促進(jìn)血管生成，促進(jìn)膠質(zhì)母細(xì)胞瘤的增殖 [28, 29]。另有研究證實(shí)，通過(guò)敲低膠質(zhì)母細(xì)胞瘤細(xì)胞的SLC7A11表達(dá)，或采用Nutlin-3a釋放出p53負(fù)性調(diào)節(jié)SLC7A11，細(xì)胞中脂氧合酶ALOXE3的活性增加，促進(jìn)膠質(zhì)母細(xì)胞瘤鐵死亡，抑制小鼠原位腫瘤的生長(zhǎng)和遷移 [30]。構(gòu)建SLC7A11基因敲除及過(guò)表達(dá)的U251膠質(zhì)瘤細(xì)胞發(fā)現(xiàn)，SLC7A11基因敲除可增加ROS水平，降低GSH水平，促進(jìn)細(xì)胞死亡；SLC7A11過(guò)表達(dá)可增加癌細(xì)胞對(duì)抗氧化應(yīng)激，對(duì)替莫唑胺（Temozolomide）的敏感性減弱 [29]。
4.2 SLC7A11與乳腺癌及生殖系統(tǒng)腫瘤
據(jù)報(bào)道，IGF-I可激活雌激素受體陽(yáng)性（estrogen receptor-positive，ER+）乳腺癌細(xì)胞中SLC7A11的表達(dá)，調(diào)節(jié)胱氨酸攝取和細(xì)胞氧化還原狀態(tài)，促進(jìn)ER+乳腺癌細(xì)胞增殖，該過(guò)程可被柳氮磺吡啶（SSZ）抑制 [31]；一種針對(duì)SLC7A11的病毒樣顆粒（virus-like-particle，VLP）AX09-0M6，采用VLP免疫方法抑制乳腺癌移植瘤小鼠的SLC7A11活性后，研究人員發(fā)現(xiàn)AX09-0M6對(duì)乳腺癌的生長(zhǎng)和肺轉(zhuǎn)移有明顯抑制作用；采用牛皰疹病毒4型（BoHV-4）載體的抗SLC7A11病毒疫苗，它能夠向體內(nèi)傳遞細(xì)胞并賦予腫瘤抗原免疫原性，靶向作用于乳腺CSCs，抑制乳腺癌進(jìn)展和轉(zhuǎn)移，這種疫苗或可作為預(yù)防乳腺癌復(fù)發(fā)的潛在選擇 [32]。在卵巢癌中，奧拉帕利（Olaparib）以p53依賴的方式，降低SLC7A11蛋白的表達(dá)水平，促進(jìn)鐵死亡，抑制腫瘤進(jìn)展 [33]。
4.3 SLC7A11與呼吸系統(tǒng)腫瘤
多種肺癌亞型中SLC7A11均有表達(dá)。在肺癌中，鐵死亡誘導(dǎo)劑Erastin，可誘導(dǎo)肺癌細(xì)胞鐵死亡，隨藥物濃度的增高，細(xì)胞死亡率也增高 [34]。在KRAS突變的肺腺癌中，SLC7A11抑制劑選擇性地增加了含有KRAS突變的肺腺癌的代謝應(yīng)激和氧化應(yīng)激介導(dǎo)的細(xì)胞死亡 [35]。另有報(bào)道，SLC7A11通過(guò)增強(qiáng)GSH合成，而對(duì)KRAS誘導(dǎo)的致瘤性至關(guān)重要 [10]。此外，SSZ通過(guò)抑制Xc-系統(tǒng)，可降低小細(xì)胞肺癌細(xì)胞內(nèi)GSH水平，抑制癌細(xì)胞生長(zhǎng)。在人喉鱗狀細(xì)胞癌中，SLC7A1敲低，顯著抑制腫瘤細(xì)胞G1至S相轉(zhuǎn)變，證實(shí)下調(diào)SLC7A11，誘導(dǎo)G1相細(xì)胞周期停滯，抑制細(xì)胞增殖，表明SLC7A11可能是人喉鱗狀細(xì)胞癌診斷和預(yù)后的重要生物標(biāo)志物 [36]。
4.5 SLC7A11與消化系統(tǒng)腫瘤
在胃癌中，敲低MGC380細(xì)胞的生長(zhǎng)分化因子15（GDF-15），導(dǎo)致SLC7A11表達(dá)下調(diào)，也促進(jìn)Erastin誘導(dǎo)的胃癌細(xì)胞鐵死亡，但不影響其它鐵死亡相關(guān)基因，如GPX4、轉(zhuǎn)鐵蛋白、鐵調(diào)素（Hepcidin）等 [37]。在胃癌小鼠模型中，采用SSZ抑制SLC7A11或?qū)D44基因切除，均可抑制胃癌細(xì)胞的生長(zhǎng)。在吉西他濱（Gemcitabine）耐藥的胰腺癌細(xì)胞中，SLC7A11表達(dá)上調(diào)，采用SSZ抑制SLC7A11與吉西他濱聯(lián)合，抑制人胰腺癌細(xì)胞系PANC-1免疫缺陷小鼠異種移植瘤的生長(zhǎng)，并增加腫瘤對(duì)Gemcitabine的敏感性。因此，基于靶向SLC7A11抑制劑的聯(lián)合用藥，有助于逆轉(zhuǎn)胰腺癌細(xì)胞的Gemcitabine耐藥 [10, 39, 40]。
5. SLC7A11的臨床應(yīng)用前景
來(lái)自Pharmsnap的數(shù)據(jù)顯示，已有1款靶向SLC7A11抗體在研臨床藥物（Anti-xCT antibody-drug conjugate (Agilvax)）處于臨床前，用于腫瘤治療。目前，SLC7A11已被廣泛賦予各種癌癥類(lèi)型的化療耐藥性。多項(xiàng)研究證實(shí)，靶向SLC7A11可以逆轉(zhuǎn)惡性腫瘤治療過(guò)程中的耐藥性。因此，SLC7A11抑制劑可以與臨床一線化療藥物進(jìn)行聯(lián)合使用，以達(dá)到作用更持久、靶向性更強(qiáng)、不良反應(yīng)更低的抗腫瘤作用。此外，SLC7A11廣泛分布于多種惡性腫瘤中，在惡性腫瘤代謝調(diào)控中的作用提示，SLC7A11可作為腫瘤治療的潛在靶點(diǎn)。
為鼎力協(xié)助各藥企針對(duì)SLC7A11在各種腫瘤等疾病在臨床中的研究，CUSABIO推出SLC7A11蛋白產(chǎn)品，跨膜次數(shù)高達(dá)12次（Code：CSB-CF892171HU(A4)），助力您在SLC7A11機(jī)制方面的研究或其潛在臨床價(jià)值的探索。
Recombinant Human SLC7A11 (CSB-CF892171HU(A4))
● SDS Assay & High Specificity Validated by Western Blot
參考文獻(xiàn)：
[1] Stockwell, Brent R. "Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications." Cell 185.14 (2022): 2401- 2421.
[2] Liu, Xiaodong. "SLC family transporters. "Drug Transporters in Drug Disposition, Effects and Toxicity (2019): 101-202.
[3] Rives, Marie-Laure, Jonathan A. Javitch, and Alan D. Wickenden. "Potentiating SLC transporter activity: emerging drug discovery opportunities." Biochemical pharmacology 135 (2017): 1-11.
[4] Mariem, O. Ben, et al. "Deciphering the ligand/xenobiotic molecular recognition mechanism in SLC transporters via a new structural binding site analysis." (2021).
[5] Li, Qiao, et al. "Subcellular drug distribution: mechanisms and roles in drug efficacy, toxicity, resistance, and targeted delivery." Drug Metabolism Reviews 50.4 (2018): 430-447.
[6] Liu, Xiaodong. "Transporter-mediated drug-drug interactions and their significance. "Drug Transporters in Drug Disposition, Effects and Toxicity ( 2019): 241-291.
[7] Zhou, Shiwei, and Yan Shu. "Transcriptional Regulation of Solute Carrier Drug Transporters." Drug Metabolism and Disposition 50.9 (2022): 1238-1250.
[8] César-Razquin, Adrián, et al. "A call for systematic research on solute carriers." cell 162.3 (2015): 478-487.
[9] Bassi, Maria, et al. "Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc-." Pflügers Archiv 442.2 (2001): 286-296.
[10] Lin, Wenyu, et al. "SLC7A11/xCT in cancer: biological functions and therapeutic implications." American journal of cancer research 10.10 (2020): 3106.
[11] Koppula, Pranavi, et al. "Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer." Cancer Communications 38.1 (2018): 1-13.
[12] He, Jiaqin, et al. "The amino acid transporter SLC7A11-mediated crosstalk implicated in cancer therapy and the tumor microenvironment." Biochemical Pharmacology (2022): 115241.
[13] Li, Sijia, et al. "The Role of SLC7A11 in Cancer: Friend or Foe?" Cancers 14.13 (2022): 3059.
[14] Lin, Yi, et al. "Pan-Cancer Analyses Confirmed the Ferroptosis-Related Gene SLC7A11 as a Prognostic Biomarker for Cancer." International Journal of General Medicine 15 (2022): 2501.
[15] Koppula, Pranavi, Li Zhuang, and Boyi Gan. "Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy." Protein & cell 12.8 (2021): 599-620.
[16] Iida, Yuko, et al. "Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane." Oncology letters 21.1 (2021): 1- 1.
[17] Xu, Xiaotian, et al. "Targeting SLC7A11 specifically suppresses the progression of colorectal cancer stem cells via inducing ferroptosis." European Journal of Pharmaceutical Sciences 152 (2020): 105450.
[18] Chen, Liang, et al. "GDF15 knockdown promotes erastin-induced ferroptosis by decreasing SLC7A11 expression." Biochemical and Biophysical Research Communications 526.2 (2020): 293-299.
[19] Chen, Qianping, et al. "SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma." Cell Death & Differentiation (2022): 1-15.
[20] Guan, Zhenhua, et al. "Tanshinone IIA induces ferroptosis in gastric cancer cells through p53-mediated SLC7A11 down-regulation." Bioscience reports 40.8 (2020).
[21] Luo, Yi, et al. "Bavachin induces ferroptosis through the STAT3/P53/SLC7A11 axis in osteosarcoma cells." Oxidative medicine and cellular longevity 2021 (2021).
[22] Sehm, Tina, et al. "Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis." oncotarget 7.46 (2016): 74630.
[23] Hu, Zhifang, et al. "A potential mechanism of temozolomide resistance in glioma-ferroptosis." Frontiers in oncology 10 (2020): 897.
[24] An, Lifeng, et al. "lncRNA AGAP2-AS1 Facilitates Tumorigenesis and Ferroptosis Resistance through SLC7A11 by IGF2BP2 Pathway in Melanoma." Computational and Mathematical Methods in Medicine 2022 (2022).
[25] Drayton, Ross M., et al. "Reduced Expression of miRNA-27a Modulates Cisplatin Resistance in Bladder Cancer by Targeting the Cystine/Glutamate Exchanger SLC7A11Cisplatin Resistance in Bladder Cancer." clinical cancer research 20.7 (2014): 1990-2000.
[26] Yadav, Poonam, et al. "SLC7A11/xCT is a target of miR-5096 and its restoration partially rescues miR-5096-mediated ferroptosis and anti-tumor effects in human breast cancer cells." Cancer Letters 522 (2021): 211-224.
[27] Sun, Chen, et al. "Propofol Inhibits Proliferation and Augments the Anti-Tumor Effect of Doxorubicin and Paclitaxel Partly Through Promoting Ferroptosis in Triple-Negative Breast Cancer Cells." Frontiers in Oncology 12 (2022): 837974-837974.
[28] Polewski, Monika D., et al. "SLC7A11 overexpression in glioblastoma is associated with increased cancer stem cell-like properties." Stem Cells and Development 26.17 (2017): 1236-1246.
[29] Polewski, Monika D., et al. "Increased expression of system xc- in glioblastoma confers an altered metabolic state and temozolomide resistance." Molecular Cancer Research 14.12 (2016): 1229-1242.
[30] Yang, Xinzhi, et al. "miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities." Oncogenesis 10.2 (2021): 1-13.
[31] Yang, Y., M. A. Becker, and D. Yee. "P2-03-03: An Insulin-Like Growth Factor I (IGF-I)-Induced Gene, Solute Carrier Family 7 Member 11 (SLC7A11)/xCT, Mediates IGF-I-Induced Biological Behaviors in Breast Cancer Cells." Cancer Research 71.24_Supplement (2011): P2-03.
[32] Wang, Zhanyu, Qianjin Jiang, and Chenfang Dong. "Metabolic reprogramming in triple-negative breast cancer. "Cancer Biology & Medicine 17.1 (2020 ): 44.
[33] Hong, Ting, et al. "PARP inhibition promotes ferroptosis via repressing SLC7A11 and synergizes with ferroptosis inducers in BRCA-proficient ovarian cancer." Redox biology 42 (2021): 101928.
[34] Huang, Chaoli, et al. "Upregulation and activation of p53 by erastin-induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells." Oncology reports 40.4 (2018): 2363-2370.
[35] Hu, Kewen, et al. "Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma." the Journal of clinical investigation 130.4 (2020): 1752-1766.
[36] Ma, Zhihong, et al. "SLC7A11, a component of cysteine/glutamate transporter, is a novel biomarker for the diagnosis and prognosis in laryngeal squamous cell carcinoma." Oncology Reports 38.5 (2017): 3019-3029.
[37] Chen, Liang, et al. "GDF15 knockdown promotes erastin-induced ferroptosis by decreasing SLC7A11 expression." Biochemical and Biophysical Research Communications 526.2 (2020): 293-299.
[38] Toyoshima, Kosei, et al. "Analysis of circulating tumor cells derived from advanced gastric cancer." international journal of cancer 137.4 (2015): 991 -998.
[39] Tang, Rong, et al. "The role of ferroptosis regulators in the prognosis, immune activity and gemcitabine resistance of pancreatic cancer." Annals of translational medicine 8.21 (2020).
[40] Tang, Rong, et al. "The role of ferroptosis regulators in the prognosis, immune activity and gemcitabine resistance of pancreatic cancer." Annals of translational medicine 8.21 (2020).
[41] Tu, H., et al. "Insights into the novel function of system Xc-in regulated cell death." Eur Rev Med Pharmacol Sci 25.3 (2021): 1650-1662.
