Ju Huai-Qiang, Lu Yun-Xin, Chen Dong-Liang, Tian Tian, Mo Hai-Yu, Wei Xiao-Li, Liao Jian-Wei, Wang Feng, Zeng Zhao-Lei, Pelicano Helene, Aguilar Mitzi, Jia Wei-Hua, Xu Rui-Hua
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.; 2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Theranostics. 2016 May 23;6(8):1160-75. doi: 10.7150/thno.14848. eCollection 2016.
Colorectal cancer (CRC) is a common neoplastic disease and a frequent cause of death. Drug resistance is a major challenge to CRC treatment and stem-like side-population (SP) cells may play a key role in this resistance. Although it has been recognized that cancer stem cells may be affected by redox status, the underlying mechanisms for this effect and the roles of celllular redox adaptation and antioxidant capacity in CRC remain elusive. Our study shows that CRC SP cells are highly dependent on cellular GSH to maintain ROS levels below those of non-SP cells. Exposing CRC cells to H2O2 produced a significant decrease in the percentage of SP cells, which was rescued by adding N-acetylcysteine. Mechanistically, CD44v interacts with and stabilizes xCT and thereby promotes the uptake of cysteine for GSH synthesis and stimulates SP cell enrichment. Additionally, miR-1297 levels were inversely correlated with the expression of xCT; thus, reduced miR-1297 contributes to SP cell enrichment in CRC tumors, which results in tumor aggressiveness and poor clinical outcomes. Importantly, redox modification by PEITC significantly reduces CRC SP cells in vitro and impairs tumors growth in vivo. The combination of 5FU and PEITC led to synergistic cytotoxic effects against CRC cells in vitro and in vivo. Taken together, our data suggest that a GSH-mediated reduction in cellular ROS levels is an essential regulator of CRC SP cells mediated by the CD44v-xCT axis, and disrupting the redox status may eliminate the chemotherapy-resistant CRC SP cells with potentially significant benefits for cancer treatment.
结直肠癌（CRC）是一种常见的肿瘤性疾病，也是常见的死亡原因。耐药性是CRC治疗的主要挑战，而干细胞样侧群（SP）细胞可能在这种耐药性中起关键作用。尽管人们已经认识到癌症干细胞可能受氧化还原状态的影响，但这种影响的潜在机制以及细胞氧化还原适应和抗氧化能力在CRC中的作用仍不清楚。我们的研究表明，CRC SP细胞高度依赖细胞内谷胱甘肽（GSH）来维持活性氧（ROS）水平低于非SP细胞。将CRC细胞暴露于过氧化氢（H2O2）会使SP细胞百分比显著降低，而添加N-乙酰半胱氨酸可使其恢复。从机制上讲，CD44v与xCT相互作用并使其稳定，从而促进半胱氨酸摄取以合成GSH，并刺激SP细胞富集。此外，miR-1297水平与xCT的表达呈负相关；因此，miR-1297的减少有助于CRC肿瘤中SP细胞的富集，这导致肿瘤侵袭性增加和临床预后不良。重要的是，异硫氰酸苯乙酯（PEITC）介导的氧化还原修饰在体外显著减少CRC SP细胞，并在体内抑制肿瘤生长。5-氟尿嘧啶（5FU）和PEITC联合使用在体外和体内对CRC细胞产生协同细胞毒性作用。综上所述，我们的数据表明，GSH介导的细胞内ROS水平降低是由CD44v-xCT轴介导的CRC SP细胞的重要调节因子，破坏氧化还原状态可能消除化疗耐药的CRC SP细胞，对癌症治疗可能具有显著益处。
