Participation of xCT in melanoma cell proliferation in vitro and tumorigenesis in vivo.
Participation of xCT in melanoma cell proliferation in vitro and tumorigenesis in vivo.
复制标题
DOI：
10.1038/s41389-018-0098-7
复制
发表时间：
2018-11-14
期刊：
影响因子：
6.2
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Shin SS;Jeong BS;Wall BA;Li J;Shan NL;Wen Y;Goydos JS;Chen S
我们的研究小组证明，谷氨酸信号抑制剂利鲁唑可减少体外黑色素瘤细胞增殖和体内肿瘤进展。利鲁唑的潜在机制在很大程度上尚不清楚。对两种人黑色素瘤细胞系的微阵列分析表明，利鲁唑刺激胱氨酸-谷氨酸氨基酸逆向转运蛋白 xCT (SLC7A11) 的表达。对培养的人黑色素瘤或正常黑色素细胞的蛋白质免疫印迹分析表明，xCT 在大多数黑色素瘤中显着过表达，但在正常细胞中则不然。使用人类肿瘤活检样本的研究表明，xCT 的过度表达与癌症分期和进展相关。为了进一步研究 xCT 是否参与黑色素瘤细胞生长，我们通过将外源 xCT 转染到最初表现出非常低的 xCT 表达的黑色素瘤细胞，衍生了几个稳定的克隆。 xCT 表达升高在体外促进细胞增殖，相反，这些黑色素瘤克隆响应利鲁唑治疗而表现出细胞增殖的剂量依赖性下降。异种移植研究表明，与载体对照相比，这些克隆以更高的速率形成极具侵袭性的肿瘤。相反，用利鲁唑治疗异种移植动物会下调 xCT 表达，表明 xCT 是利鲁唑的分子靶点。此外，参加利鲁唑单药治疗 II 期临床试验的患者肿瘤活检的蛋白质裂解物显示，疾病稳定患者的治疗后标本中 xCT 水平降低。综上所述，我们的结果表明 xCT 可用作监测接受利鲁唑化疗患者的标志物。
Our research group demonstrated that riluzole, an inhibitor of glutamatergic signaling reduced melanoma cell proliferation in vitro and tumor progression in vivo. The underlying mechanisms of riluzole are largely unknown. Microarray analyses on two human melanoma cell lines revealed that riluzole stimulates expression of the cystine-glutamate amino acid antiporter, xCT (SLC7A11). Western immunoblot analysis from cultured human melanoma or normal melanocytic cells showed that xCT was significantly overexpressed in most melanomas, but not normal cells. Studies using human tumor biopsy samples demonstrated that overexpression of xCT was correlated with cancer stage and progression. To further investigate if xCT is involved in melanoma cell growth, we derived several stable clones through transfection of exogenous xCT to melanoma cells that originally showed very low expression of xCT. The elevated xCT expression promoted cell proliferation in vitro and inversely, these melanoma clones showed a dose-dependent decrease in cell proliferation in response to riluzole treatment. Xenograft studies showed that these clones formed very aggressive tumors at a higher rate compared to vector controls. Conversely, treatment of xenograft-bearing animals with riluzole down-regulated xCT expression suggesting that xCT is a molecular target of riluzole. Furthermore, protein lysates from tumor biopsies of patients that participated in a riluzole monotherapy phase II clinical trial showed a reduction in xCT levels in post-treatment specimens from patients with stable disease. Taken together, our results show that xCT may be utilized as a marker to monitor patients undergoing riluzole-based chemotherapies.
登录
查看更多内容
黑色素瘤中谷氨酸成瘾的基础谷氨酸和天冬酸酯蛋白催化剂。
影响因子：
--
作者：
Ratnikov B;Aza-Blanc P;Ronai ZA;Smith JW;Osterman AL;Scott DA
通讯作者：
Scott DA
DOI：
10.1111/j.1600-0749.2005.00284.x
发表时间：
2006-02-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
--
作者：
Hoogduijn, MJ;Hitchcock, IS;Genever, PG
通讯作者：
Genever, PG
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki
影响因子：
30.8
作者：
Pollock, PM;Cohen-Solal, K;Chen, S
通讯作者：
Chen, S
影响因子：
8
作者：
Chen, R-S;Song, Y-M;Li, W.
通讯作者：
Li, W.