xCT与肿瘤和肿瘤干细胞关系的研究进展

doi:10.13481/j.1671-587x.20190646

摘要/Abstract

摘要： 胱氨酸/谷氨酸逆向转运体（system xc^-）是细胞膜上的逆向转运氨基酸的异源二聚体，参与氧化还原和氨基酸转运的调控。胱氨酸/谷氨酸反向运输溶质载体家族7成员11（SLC7A11）也称为xCT，为其主要功能性亚基。由于肿瘤组织中氧化应激的增强及营养代谢需求的增加，xCT在多种肿瘤细胞中呈异常表达。在肿瘤细胞中，xCT通过摄取胱氨酸还原为半胱氨酸用于谷胱甘肽的合成，参与肿瘤耐药；同时胞浆内多余的半胱氨酸分泌到细胞外，提供细胞信号传导和细胞间通讯所需的还原微环境，有利于肿瘤细胞的增殖、侵袭和转移。在肿瘤干细胞（CSC）中，xCT促进CSC表面标记蛋白的表达，与维持CSC的干性特征密切相关，是肿瘤治疗的潜在靶点之一，并且有望应用于肿瘤的临床筛查。现通过回顾近年来xCT的相关研究，就xCT在肿瘤和CSC中的生物学作用及其作用机制进行综述。

关键词: 胱氨酸/谷氨酸逆向转运体, 肿瘤, 氧化应激, 肿瘤干细胞, xCT

中图分类号:

R730.2

熊芳, 龙梅芳, 叶小群. xCT与肿瘤和肿瘤干细胞关系的研究进展[J]. 吉林大学学报(医学版), 2019, 45(06): 1459-1464.

参考文献

[1] KOPPULA P, ZHANG Y, ZHUANG L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer[J]. Cancer Commun (Lond), 2018, 38(1): 12.
[2] LEWERENZ J, HEWETT S J, HUANG Y, et al. The Cystine/Glutamate antiporter system xc^- in health and disease: From molecular mechanisms to novel therapeutic opportunities[J]. Antioxid Redox Sign, 2013, 18(5): 522-555.
[3] LIM J C, DONALDSON P J. Focus on molecules: The cystine/glutamate exchanger (System x(c)(-))[J]. Exp Eye Res, 2011, 92(3): 162-163.
[4] SHIN C S, MISHRA P, WATROUS J D, et al. The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility[J]. Nat Commun, 2017, 8: 15074.
[5] CHEN D, TAVANA O, CHU B, et al. NRF2 is a major target of ARF in p53-Independent tumor suppression[J]. Mol Cell, 2017, 68(1): 224-232.
[6] LEWERENZ J, MAHER P. Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression[J]. J Biol Chem, 2009, 284(2): 1106-1115.
[7] CLEMONS N J, LIU D S, DUONG C P, et al. Inhibiting system xC(-) and glutathione biosynthesis-a potential Achilles’ heel in mutant-p53 cancers[J]. Mol Cell Oncol, 2017, 4(5): e1344757.
[8] YANG Y, YEE D. IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC[J]. Cancer Res, 2014, 74(8): 2295-2305.
[9] WANG X, LI Y, WANG H, et al. Propofol inhibits invasion and proliferation of C6 glioma cells by regulating the Ca²⁺ permeable AMPA receptor-system x c^- pathway[J]. Toxicol in Vitro, 2017, 44: 57-65.
[10] PAKOS-ZEBRUCKA K, KORYGA I, MNICH K, et al. The integrated stress response[J]. Embo Rep, 2016, 17(10): 1374-1395.
[11] YE P, MIMURA J, OKADA T, et al. Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of t24 bladder carcinoma cells to proteasome inhibition[J]. Mol Cell Biol, 2014, 34(18): 3421-3434.
[12] MARTIN L, GARDNER L B. Stress-induced inhibition of nonsense-mediated RNA decay regulates intracellular cystine transport and intracellular glutathione through regulation of the cystine/glutamate exchanger SLC7A11[J]. Oncogene, 2015, 34(32): 4211-4218.
[13] DRAYTON R M, DUDZIEC E, PETER S, et al. Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11[J]. Clin Cancer Res, 2014, 20(7): 1990-2000.
[14] LIU X X, LI X J, ZHANG B, et al. MicroRNA-26b is underexpressed in human breast cancer and induces cell apoptosis by targeting SLC7A11[J]. Febs Lett, 2011, 585(9): 1363-1367.
[15] WU Y, SUN X, SONG B, et al. MiR-375/SLC7A11 axis regulates oral squamous cell carcinoma proliferation and invasion[J]. Cancer Med, 2017, 6(7): 1686-1697.
[16] ISHIMOTO T, NAGANO O, YAE T, et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc^- and thereby promotes tumor growth[J]. Cancer Cell, 2011, 19(3): 387-400.
[17] GU Y, ALBUQUERQUE C P, BRAAS D, et al. MTORC2 regulates amino acid metabolism in cancer by phosphorylation of the Cystine-Glutamate antiporter xCT[J]. Mol Cell, 2017, 67(1): 128-138.
[18] JI X, QIAN J, RAHMAN S, et al. XCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression[J]. Oncogene, 2018, 37(36): 5007-5019.
[19] ZHONG W, WEISS H L, JAYSWAL R D, et al. Extracellular redox state shift: A novel approach to target prostate cancer invasion[J]. Free Radical Bio Med, 2018, 117: 99-109.
[20] 郑雪婷,赵飞,赵瑞,等. xCT调节乳腺癌细胞转移的作用机制研究[J]. 军事医学,2015(5): 334-338.
[21] 李杨,齐建利,赵立平,等. xCT影响肝癌细胞转移的作用机制研究[J]. 天津医科大学学报,2014(2): 93-97.
[22] KINOSHITA H, OKABE H, BEPPU T, et al. Cystine/glutamic acid transporter is a novel marker for predicting poor survival in patients with hepatocellular carcinoma[J]. Oncol Rep, 2013, 29(2): 685-689.
[23] MA Z, ZHANG H, LIAN M, et al. SLC7A11, a component of cysteine/glutamate transporter, is a novel biomarker for the diagnosis and prognosis in laryngeal squamous cell carcinoma[J]. 2017, 38(5): 3019-3029.
[24] LEE J R, ROH J L, LEE S M, et al. Overexpression of cysteine-glutamate transporter and CD44 for prediction of recurrence and survival in patients with oral cavity squamous cell carcinoma[J]. Head Neck, 2018.DOI:10.1002/hed.25331
[25] OTSUBO K, NOSAKI K, IMAMURA C K, et al. Phase Ⅰ study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer[J]. Cancer Sci, 2017, 108(9): 1843-1849.
[26] POLEWSKI M D, REVERON-THORNTON R F, CHERRYHOLMES G A, et al. Increased expression of system xc^- in glioblastoma confers an altered metabolic state and temozolomide resistance[J]. Mol Cancer Res, 2016, 14(12): 1229-1242.
[27] MAUGERI-SACCA M, VIGNERI P, De MARIA R. Cancer stem cells and chemosensitivity[J]. Clin Cancer Res, 2011, 17(15): 4942-4947.
[28] YE X Q, LI Q, WANG G H, et al. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells[J]. Int J Cancer, 2011, 129(4): 820-831.
[29] POLEWSKI M D, REVERON-THORNTON R F, CHERRYHOLMES G A, et al. SLC7A11 overexpression in glioblastoma is associated with increased cancer stem cell-like properties[J]. Stem Cells Dev, 2017, 26(17): 1236-1246.
[30] THANEE M, LOILOME W, TECHASEN A, et al. CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: A target for cholangiocarcinoma treatment[J]. Cancer Sci, 2016, 107(7): 991-1000.
[31] SHITARA K, DOI T, NAGANO O, et al. Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407)[J]. Gastric Cancer, 2017, 20(6): 1004-1009.
[32] OTSUBO K, NOSAKI K, IMAMURA C K, et al. Phase Ⅰ study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer[J]. Cancer Sci, 2017, 108(9): 1843-1849.
[33] TAKAYAMA T, KUBO T, MORIKAWA A, et al. Potential of sulfasalazine as a therapeutic sensitizer for CD44 splice variant 9-positive urogenital cancer[J]. Med Oncol, 2016, 33(5): 45.
[34] LU H, SAMANTA D, XIANG L, et al. Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype[J]. Proc Natl Acad Sci U S A, 2015, 112(33): E4600-E4609.
[35] KOGLIN N, MUELLER A, BERNDT M, et al. Specific PET imaging of xC-transporter activity using a (1)(8)F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism[J]. Clin Cancer Res, 2011, 17(18): 6000-6011.
[36] BAEK S, MUELLER A, LIM Y S, et al. (4S)-4-(3-18F-fluoropropyl)-L-glutamate for imaging of xC transporter activity in hepatocellular carcinoma using PET: Preclinical and exploratory clinical studies[J]. J Nucl Med, 2013, 54(1): 117-123.
[37] KAVANAUGH G, WILLIAMS J, MORRIS A S, et al. Utility of ¹⁸F-FSPG PET to image hepatocellular carcinoma: First clinical evaluation in a US population[J]. Mol Imaging Biol, 2016, 18(6): 924-934.
[38] MITTRA E S, KOGLIN N, MOSCI C, et al. Pilot preclinical and clinical evaluation of (4S)-4-(3-[18F]fluoropropyl)-L-Glutamate (¹⁸F-FSPG) for PET/CT imaging of intracranial malignancies[J]. PLoS One, 2016, 11(2): e148628.
[39] BAEK S, CHOI C M, AHN S H, et al. Exploratory clinical trial of (4S)-4-(3-¹⁸F fluoropropyl)-L-glutamate for imaging xC-transporter using positron emission tomography in patients with Non-Small cell lung or breast cancer[J]. Clin Cancer Res, 2012, 18(19): 5427-5437.
[40] MA M Z, CHEN G, WANG P, et al. Xc-inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH-dependent mechanism[J]. Cancer Lett, 2015, 368(1): 88-96.
[41] LO M, LING V, LOW C, et al. Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer[J]. Curr Oncol, 2010, 17(3): 9-16.
[42] SONG Y, JANG J, SHIN T H, et al. Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells[J]. J Exp Clin Cancer Res, 2017, 36(1): 38.
[43] HARYU S, SAITO R, JIA W, et al. Convection-enhanced delivery of sulfasalazine prolongs survival in a glioma stem cell brain tumor model[J]. J Neurooncol, 2018, 136(1): 23-31.
[44] RODMAN S N, SPENCE J M, RONNFELDT T J, et al. Enhancement of radiation response in breast cancer stem cells by inhibition of thioredoxin- and Glutathione-Dependent metabolism[J]. Radiat Res, 2016, 186(4): 385-395.
[45] SEISHIMA R, OKABAYASHI K, NAGANO O, et al. Sulfasalazine, a therapeutic agent for ulcerative colitis, inhibits the growth of CD44v9(+) cancer stem cells in ulcerative colitis-related cancer[J]. Clin Res Hepatol Gastroenterol, 2016, 40(4): 487-493.