FoxM1-dependent and fatty acid oxidation-mediated ROS modulation is a cell-intrinsic drug resistance mechanism in cancer stem-like cells
FoxM1-dependent and fatty acid oxidation-mediated ROS modulation is a cell-intrinsic drug resistance mechanism in cancer stem-like cells
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DOI：
10.1016/j.redox.2020.101589
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Cheong, Jae-Ho
中科院分区：
文献类型：
--
作者：
Choi, Hae-Ji;Jhe, Yoo-Lim;Cheong, Jae-Ho
氧化磷酸化(OXPHOS)和活性氧簇(ROS)水平的增加是内在联系的。ROS是重要的信号分子，在化疗过程中过量产生时会产生有害影响，导致细胞死亡。肿瘤干细胞(CSCs)是一类对化疗耐药的肿瘤细胞亚群，具有高度侵袭性和转移性，可导致恶性肿瘤的发生。在这项研究中，我们证明了CSCs表现出OXPHOS增加，但ROS水平却反常地低。考虑到大量ROS的有害影响，CSCs已经开发出潜在的机制来猝灭过量的ROS以维持氧化还原动态平衡。我们的目的是研究胃CSCs中ROS的独特代谢特征和调节机制，并探索针对CSCs的潜在治疗策略。对人胃癌细胞株AGS和MKN1进行了基于液-质联用的代谢组学和基因芯片分析。用流式细胞仪分析线粒体质量、膜电位和ROS等线粒体特性。OXPHOS水平升高的CSCs通过结合FOXM1依赖的Prx3表达和脂肪酸氧化介导的NADPH再生来维持低ROS水平。因此，针对CSCs中ROS稳态的干预措施可能是针对这一耐药肿瘤细胞亚群的有用策略。
Increased oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) levels are inherently linked. ROS are essential signaling molecules, with detrimental effects when produced in excess during chemotherapy, leading to cell death. Cancer stem-like cells (CSCs) are a subpopulation of tumor cells resistant to chemotherapy, highly invasive and metastagenic, driving malignant cancer behavior. In this study, we demonstrated that CSCs exhibit increased OXPHOS but paradoxically low ROS levels. Considering the detrimental effects of large amounts of ROS, CSCs have developed potential mechanisms for quenching excess ROS to maintain redox homeostasis. We aimed to investigate the distinct metabolic features and mechanisms of ROS regulation in gastric CSCs and explore potential therapeutic strategies targeting CSCs. Human gastric cancer cell lines, AGS and MKN1, were subjected to liquid chromatography/mass spectrometry-based metabolomic and microarray analyses. Mitochondrial properties such as mitochondrial mass, membrane potential, and ROS were assessed by flow cytometric analysis. CSCs with increased OXPHOS levels maintained low ROS levels by coupling FoxM1 dependent Prx3 expression and fatty acid oxidation-mediated NADPH regeneration. Thus, interventions targeting ROS homeostasis in CSCs may be a useful strategy for targeting this drug-resistant tumor cell sub population.