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FoxM1-dependent and fatty acid oxidation-mediated ROS modulation is a cell-intrinsic drug resistance mechanism in cancer stem-like cells

 Hae-Ji Choi  ;  Yoo-Lim Jhe  ;  Jungmin Kim  ;  Ju Yeon Lim  ;  Jae Eun Lee  ;  Min-Kyue Shin  ;  Jae-Ho Cheong 
 REDOX BIOLOGY, Vol.36 : 101589, 2020-09 
Journal Title
Issue Date
Cancer stem-like cell ; Fatty acid oxidation ; FoxM1 ; NADPH ; Oxidative phosphorylation ; Prx3 ; Reactive oxygen species
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 subpopulation.
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jae Eun(이재은)
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
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