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            Your Good Partner in Biology Research

            SLC7A11:SLC家族氨基酸轉運蛋白,抗鐵死亡!腫瘤耐藥新方向!

            瀏覽次數:572      日期:2022-10-13 13:46:09

            近期,Cell 雜志推出重磅“鐵死亡”綜述,紀念鐵死亡十周年 [1]!該文章主要介紹了鐵死亡的關鍵調控因子,以及未來利用鐵死亡來促進治療方面的前景。SLC7A11作為鐵死亡的最關鍵的上游調節因子之一,近年來,大量文獻早已揭示SLC7A11驅動鐵死亡抗性,在腫瘤等疾病中發揮調控作用。SLC7A11不僅是鐵死亡的有效靶標,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、結直腸癌、膠質瘤等等。到目前為止,研究學者已經探索多種抗癌方法,然而,有效治療的一個主要障礙是對抗癌治療的適應性耐藥性。SLC7A11對于這一障礙所帶來的影響,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制又如何?今天我們一起來了解一下。


            1. 什么是溶質轉運蛋白SLC?

            溶質載體(Solute Carriers, SLC),即溶質轉運蛋白超家族是人類細胞膜(含胞內膜)上最重要的膜轉運蛋白家族之一 [2]。目前已鑒定的人源SLC轉運蛋白超家族系列包含52個亞家族,共400多個成員 [2, 3]。SLC轉運蛋白超家族是僅次于G蛋白偶聯受體(GPCR)后的第二大膜蛋白家族 [4]。SLCs亞細胞分布廣泛,除可分布于細胞膜外,還可分布在細胞核膜、內質網、線粒體、溶酶體、高爾基體和過氧化物酶體等細胞器 [4, 5]。SLC作為典型的跨膜蛋白,介導各種營養物質和代謝產物的跨膜生物膜轉運,包括金屬離子、無機離子、有機離子、氨基酸、脂質、糖類、神經遞質、核酸和藥物等 [6-8] 圖1)。

            研究表明,SLCs蛋白表達異?;蚬δ苋毕菖c多種疾病的發生發展密切相關,包括腫瘤、代謝性疾病、心血管疾病、免疫系統和神經功能障礙等等,使得該家族蛋白的功能研究近年來備受關注 [7]。尤其在腫瘤中,SLC的成員作為氨基酸轉運體的主要組成部分,腫瘤細胞對于氨基酸的大量攝取主要是通過各種過表達的氨基酸轉運體實現的 [7-8]。因此,通過靶向SLC家族的氨基酸轉運體,實現對腫瘤生長的抑制成為一個有效的策略。

            溶質轉運體SLC介導的物質轉運

            圖1. 溶質轉運體SLC介導的物質轉運 [6-8]


            2. 什么是SLC7A11?

            溶質載體家族成員SLC7A11(Solute Carrier Family 7 Member 11,又名xCT)是溶質轉運第7家族的第11個成員,屬于胱氨酸/谷氨酸逆向轉運蛋白,主要參與氨基酸在質膜上的轉運 [9, 10]。SLC7A11基因位于人染色體4q28-q32,具有14個外顯子,編碼氨基酸轉運載體xCT,其蛋白由501個氨基酸組成,包括12個跨膜結構域,其N端和C端均存在于細胞質內 [9, 10, 11]圖2)。SLC7A11作為輕鏈亞基,與重鏈亞基SLC3A2組成胱氨酸/谷氨酸反轉運體(Xc-系統),但發揮主要轉運功能活性的是SLC7A11 [9-12]。近幾年的國內外研究表明,SLC7A11高表達于多種實體惡性腫瘤,如乳腺癌、胰腺癌、卵巢癌和膠質瘤等等,且與惡性腫瘤的治療耐藥性有著密切的關系 [13-14]。目前,SLC7A11已經成為抗癌治療的一個研究重點。

            SLC7A11的結構

            圖2. SLC7A11的結構 [11]


            3. SLC7A11相關的調節機制

            3.1 SLC7A11和Xc-系統

            胱氨酸/谷氨酸轉運體系統(cystine/glutamate transporter, Xc-系統)是氨基酸轉運體家族中的重要亞型。Xc-系統由輕鏈SLC7A11和重鏈SLC3A2兩種蛋白質組成 [10]。SLC3A2作為其伴侶蛋白,用于維持SLC7A11蛋白的穩定性并調節SLC7A11向質膜的運輸。輕鏈亞基SLC7A11作為Xc-系統的功能亞基,SLC7A11對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,促進谷胱甘肽(glutathione,r-glutamyl cysteingl+glycine,GSH)的合成,保護細胞免受氧化應激的損傷,維持細胞氧化還原平衡,從而阻止細胞因脂質過氧化而導致的細胞死亡 [9-12]。目前,對Xc-系統的研究主要集中于輕鏈亞基SLC7A11(圖3[41]。

            SLC7A11 在Xc-系統中發揮主要作用

            圖3. SLC7A11 在Xc-系統中發揮主要作用 [41]

            3.2 SLC7A11與鐵死亡

            SLC7A11是特異性的氨基酸轉運蛋白,也是鐵死亡的關鍵調節蛋白(點擊可查看“鐵死亡”專題文章)。SLC7A11的下調可通過抑制半胱氨酸代謝通路,導致細胞內胱氨酸水平降低和GSH生物合成耗竭,間接抑制GPX4的活性,進而導致脂質過氧化物堆積,最終誘導細胞發生鐵死亡(圖4[15, 16]。此外,經典的鐵死亡促進劑Erastin,可靶向SLC7A11,誘導鐵死亡,逆轉結直腸癌耐藥 [17, 18]。研究人員發現,過表達SOCS2可促進鐵死亡關鍵蛋白SLC7A11發生K48鏈型泛素化降解,調控肝癌中鐵死亡的發生 [19]。近期還有研究表明,活化后的腫瘤蛋白53(p53)可以結合到SLC7A11基因的啟動子區,從而抑制了SLC7A11基因的轉錄活性,影響GSH的合成,可誘導發生鐵死亡 [20, 21]。

            SLC7A11/GPX4通路在鐵死亡中的作用方式

            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介導的GSH水平升高,其過程參與化療藥物治療耐藥。例如,在膠質瘤中,SLC7A11過表達,可增加膠質瘤細胞對氧化應激的抵抗力,降低對替莫唑胺(Temozolomide)的敏感性 [22, 23]。在黑色素瘤中,SLC7A11通過增加細胞內GSH含量,使黑色素瘤對BRAF抑制劑產生耐藥性,而組蛋白去乙?;敢种苿┮种芐LC7A11能夠顯著誘導腫瘤消退 [25]。在大腸癌中,特異性SLC7A11抑制劑-柳氮磺吡啶(Sulfasalazine,SSZ),可有效增強順鉑(Cisplatin)在癌細胞內的藥物含量和細胞毒性 [12]。在膀胱癌中,下調SLC7A11表達,耐藥細胞對cisplatin的敏感性明顯增加 [25]。三陰性乳腺癌患者中,SLC7A11、ATF4的表達遠高于正常乳腺組織,eIF2α/ATF4軸上調SLC7A11的表達,促進GSH合成,抑制活性氧自由基ROS的積累,而eIF2α去磷酸化使SLC7A11表達降低,caspase-3表達增加,誘導三陰性乳腺癌細胞凋亡,使得對順鉑和多柔比星(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腫瘤的治療靶點。


            4. SLC7A11在腫瘤靶向治療中的作用

            4.1 SLC7A11與神經系統腫瘤

            研究表明,SLC7A11可作為轉錄激活因子4(ATF4)的靶標,在人膠質母細胞瘤細胞U87和U251中,過表達ATF4通過增加SLC7A11的表達,抑制腫瘤細胞發生鐵死亡,促進血管生成,促進膠質母細胞瘤的增殖 [28, 29]。另有研究證實,通過敲低膠質母細胞瘤細胞的SLC7A11表達,或采用Nutlin-3a釋放出p53負性調節SLC7A11,細胞中脂氧合酶ALOXE3的活性增加,促進膠質母細胞瘤鐵死亡,抑制小鼠原位腫瘤的生長和遷移 [30]。構建SLC7A11基因敲除及過表達的U251膠質瘤細胞發現,SLC7A11基因敲除可增加ROS水平,降低GSH水平,促進細胞死亡;SLC7A11過表達可增加癌細胞對抗氧化應激,對替莫唑胺(Temozolomide)的敏感性減弱 [29]。

            4.2 SLC7A11與乳腺癌及生殖系統腫瘤

            據報道,IGF-I可激活雌激素受體陽性(estrogen receptor-positive,ER+)乳腺癌細胞中SLC7A11的表達,調節胱氨酸攝取和細胞氧化還原狀態,促進ER+乳腺癌細胞增殖,該過程可被柳氮磺吡啶(SSZ)抑制 [31];一種針對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,研究人員發現AX09-0M6對乳腺癌的生長和肺轉移有明顯抑制作用;采用牛皰疹病毒4型(BoHV-4)載體的抗SLC7A11病毒疫苗,它能夠向體內傳遞細胞并賦予腫瘤抗原免疫原性,靶向作用于乳腺CSCs,抑制乳腺癌進展和轉移,這種疫苗或可作為預防乳腺癌復發的潛在選擇 [32]。在卵巢癌中,奧拉帕利(Olaparib)以p53依賴的方式,降低SLC7A11蛋白的表達水平,促進鐵死亡,抑制腫瘤進展 [33]。

            4.3 SLC7A11與呼吸系統腫瘤

            多種肺癌亞型中SLC7A11均有表達。在肺癌中,鐵死亡誘導劑Erastin,可誘導肺癌細胞鐵死亡,隨藥物濃度的增高,細胞死亡率也增高 [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激和氧化應激介導的細胞死亡 [35]。另有報道,SLC7A11通過增強GSH合成,而對KRAS誘導的致瘤性至關重要 [10]。此外,SSZ通過抑制Xc-系統,可降低小細胞肺癌細胞內GSH水平,抑制癌細胞生長。在人喉鱗狀細胞癌中,SLC7A1敲低,顯著抑制腫瘤細胞G1至S相轉變,證實下調SLC7A11,誘導G1相細胞周期停滯,抑制細胞增殖,表明SLC7A11可能是人喉鱗狀細胞癌診斷和預后的重要生物標志物 [36]。

            4.5 SLC7A11與消化系統腫瘤

            在胃癌中,敲低MGC380細胞的生長分化因子15(GDF-15),導致SLC7A11表達下調,也促進Erastin誘導的胃癌細胞鐵死亡,但不影響其它鐵死亡相關基因,如GPX4、轉鐵蛋白、鐵調素(Hepcidin)等 [37]。在胃癌小鼠模型中,采用SSZ抑制SLC7A11或對CD44基因切除,均可抑制胃癌細胞的生長。在吉西他濱(Gemcitabine)耐藥的胰腺癌細胞中,SLC7A11表達上調,采用SSZ抑制SLC7A11與吉西他濱聯合,抑制人胰腺癌細胞系PANC-1免疫缺陷小鼠異種移植瘤的生長,并增加腫瘤對Gemcitabine的敏感性。因此,基于靶向SLC7A11抑制劑的聯合用藥,有助于逆轉胰腺癌細胞的Gemcitabine耐藥 [10, 39, 40]。


            5. SLC7A11的臨床應用前景

            來自Pharmsnap的數據顯示,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型的化療耐藥性。多項研究證實,靶向SLC7A11可以逆轉惡性腫瘤治療過程中的耐藥性。因此,SLC7A11抑制劑可以與臨床一線化療藥物進行聯合使用,以達到作用更持久、靶向性更強、不良反應更低的抗腫瘤作用。此外,SLC7A11廣泛分布于多種惡性腫瘤中,在惡性腫瘤代謝調控中的作用提示,SLC7A11可作為腫瘤治療的潛在靶點。

            為鼎力協助各藥企針對SLC7A11在各種腫瘤等疾病在臨床中的研究,CUSABIO推出SLC7A11蛋白產品,跨膜次數高達12次(Code:CSB-CF892171HU(A4)),助力您在SLC7A11機制方面的研究或其潛在臨床價值的探索。

            Recombinant Human SLC7A11 (CSB-CF892171HU(A4))

            ● SDS Assay & High Specificity Validated by Western Blot

            ● Excellent Bioactivity Validated by Functional ELISA Blot


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