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Title:
Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer | Oncogene
Description:
Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that generates NADPH to maintain reduced glutathione (GSH), which scavenges reactive oxygen species (ROS) to protect cancer cell from oxidative damage. In this study, we mainly investigate the potential roles of G6PD in colorectal cancer (CRC) development and chemoresistance. We discover that G6PD is overexpressed in CRC cells and patient specimens. High expression of G6PD predicts poor prognosis and correlated with poor outcome of oxaliplatin-based first-line chemotherapy in patients with CRC. Suppressing G6PD decreases NADPH production, lowers GSH levels, impairs the ability to scavenge ROS levels, and enhances oxaliplatin-induced apoptosis in CRC via ROS-mediated damage in vitro. In vivo experiments further shows that silencing G6PD with lentivirus or non-viral gene delivery vector enhances oxaliplatin anti-tumor effects in cell based xenografts and PDX models. In summary, our finding indicated that disrupting G6PD-mediated NADPH homeostasis enhances oxaliplatin-induced apoptosis in CRC through redox modulation. Thus, this study indicates that G6PD is a potential prognostic biomarker and a promising target for CRC therapy.
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nature portfolio pvt1/mir-195-5p axis-dependent manner privacy policy nature bisecting glcnac-branched n-glycosylation advertising apoptotic index nadph/nadp-glo assay kit sun yat-sen university social media glucose-6-phosphate dehydrogenase expression gsh/gssg-glo assay kit enhances oxaliplatin-induced apoptosis 0/ reprints g6pd-mediated nadph homeostasis hbx-mediated nrf2 activation singlet oxygen-induced apoptosis glucose-6-phosphate dehydrogenase full size image block epithelial-mesenchymal transition platinum-based antineoplastic agent g6pd-mediated antioxidant production cell line-based xenografts c-src facilitates tumorigenesis rapid-developing field recently rate-limiting enzyme g6pd oxaliplatin-induced apoptotic cells nrf2-mediated antioxidant response student unpaired t-test log-phase g6pd knockdown pentose phosphate pathway cell line-based experiments permissions biosynthesis redox homeostasis progression-free survival curves selectively kills kras previously published reports g6pd-knockdown crc cells sorafenib induced ferroptosis g6pd-knockdown cells compared oxaliplatin-induced cytotoxicity original magnification anti-proliferative effects providing ribose phosphate induced significant increase gsh/gssg ratios potential-sensitive probe rhodamine-123 ros-mediated damage lowers gsh levels nedd8 pathway inhibition
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- Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?
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headline:Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer
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headline:Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer
description:Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that generates NADPH to maintain reduced glutathione (GSH), which scavenges reactive oxygen species (ROS) to protect cancer cell from oxidative damage. In this study, we mainly investigate the potential roles of G6PD in colorectal cancer (CRC) development and chemoresistance. We discover that G6PD is overexpressed in CRC cells and patient specimens. High expression of G6PD predicts poor prognosis and correlated with poor outcome of oxaliplatin-based first-line chemotherapy in patients with CRC. Suppressing G6PD decreases NADPH production, lowers GSH levels, impairs the ability to scavenge ROS levels, and enhances oxaliplatin-induced apoptosis in CRC via ROS-mediated damage in vitro. In vivo experiments further shows that silencing G6PD with lentivirus or non-viral gene delivery vector enhances oxaliplatin anti-tumor effects in cell based xenografts and PDX models. In summary, our finding indicated that disrupting G6PD-mediated NADPH homeostasis enhances oxaliplatin-induced apoptosis in CRC through redox modulation. Thus, this study indicates that G6PD is a potential prognostic biomarker and a promising target for CRC therapy.
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type:Organization
name:T-B Kang
affiliation:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
address:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
type:PostalAddress
type:Organization
name:D Xie
affiliation:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
address:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
type:PostalAddress
type:Organization
name:M-S Zeng
affiliation:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
address:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
type:PostalAddress
type:Organization
name:P Huang
affiliation:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
address:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
type:PostalAddress
type:Organization
email:[email protected]
name:R-H Xu
affiliation:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
address:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
name:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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