STAT3 & Cytochrome P450 2C9: A novel signaling pathway in liver cancer stem cells
STAT3 & Cytochrome P450 2C9: A novel signaling pathway in liver cancer stem cells
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DOI：
10.1016/j.biopha.2012.08.011
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发表时间：
2012-12-01
影响因子：
7.5
通讯作者：
Yu, Su Jong
中科院分区：
文献类型：
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作者：
Myung, Sun Jung;Yoon, Jung-Hwan;Yu, Su Jong
尽管癌症干细胞（CSCs）被认为是肿瘤生长和抵抗治疗的关键驱动因素，但CSCs的特异性信号传导在很大程度上是未知的。在这项研究中，我们评估了缺氧和STAT3信号在CSCs治疗抵抗中的作用。侧群体（SP）细胞分析和分选用于检测具有csc功能的亚群体。本研究使用Huh-7细胞、阿霉素、磺胺苯唑（一种CYP2C9抑制剂）和AG490（一种STAT3抑制剂）。MTS法检测细胞生长和凋亡，免疫印迹法检测凋亡和激酶信号通路。与非SP细胞相比，IL-6在SP细胞中诱导STAT3活化更为显著。低氧诱导SP细胞增殖，微阵列分析显示，低氧条件下CYP2C9的表达明显高于常氧条件下的SP细胞。虽然缺氧SP细胞对阿霉素诱导的凋亡不敏感，但磺胺苯唑预处理使缺氧SP细胞对阿霉素的细胞毒性增敏。这些结果表明STAT3对CSC存活至关重要，缺氧诱导的CYP2C9表达与缺氧条件下CSC的阿霉素耐药有关。因此，CYP2C9和STAT3的选择性抑制可能与CSCs对抗癌治疗的增敏有关，特别是在晚期病例中。(C) 2012 Elsevier Masson SAS。版权所有。
Although cancer stem cells (CSCs) are believed to be the key drivers in tumor growth and resistance to therapy, the specific signaling of CSCs is largely unknown. In this study, we evaluated the roles of hypoxia and STAT3 signaling on the treatment resistance of CSCs. Side population (SP) cell analysis and sorting were used to detect subpopulations that function as CSCs. Huh-7 cells, doxorubicin, sulfaphenazole (a CYP2C9 inhibitor), and AG490 (a STAT3 inhibitor) were used in this study. Cell growth and apoptosis were assessed using MTS assays, and apoptotic and kinase signaling pathways were explored by immunoblotting. Treatment with IL-6 induced STAT3 activation more significantly in SP than non-SP cells. Hypoxia induced SP cell proliferation, and microarray analysis showed that the expression of CYP2C9 was significantly increased in hypoxic than normoxic SP cells. Although hypoxic SP cells were less sensitive to doxorubicin-induced apoptosis, pretreatment with sulfaphenazole sensitized hypoxic SP cells to doxorubicin cytotoxicity. These results indicate that STAT3 is critical for CSC survival and hypoxia-inducible CYP2C9 expression is responsible the doxorubicin resistance of CSCs under hypoxic conditions. Thus, the selective inhibition of CYP2C9 and STAT3 may be implicated in the sensitization of CSCs to anti-cancer treatment, particularly in advanced cases. (C) 2012 Elsevier Masson SAS. All rights reserved.