期刊
CANCERS
卷 12, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/cancers12020280
关键词
NRF2; glutathione metabolism; SDHB mutation; pheochromocytoma; paraganglioma
类别
资金
- Intramural Research Program of the Center for Cancer Research, National Cancer Institute
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [ZIAHD008735] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [ZIABC011761] Funding Source: NIH RePORTER
Succinate dehydrogenase subunit B (SDHB) deficiency frequently occurs in cluster I pheochromocytomas and paragangliomas (PCPGs). SDHB-mutated PCPGs are characterized by alterations in the electron transport chain, metabolic reprogramming of the tricarboxylic cycle, and elevated levels of reactive oxygen species (ROS). We discovered that SDHB-deficient PCPG cells exhibit increased oxidative stress burden, which leads to elevated demands for glutathione metabolism. Mechanistically, nuclear factor erythroid 2-related factor 2 (NRF2)-guided glutathione de novo synthesis plays a key role in supporting cellular survival and the proliferation of SDHB-knockdown (SDHBKD) cells. NRF2 blockade not only disrupted ROS homeostasis in SDHB-deficient cells but also caused severe cytotoxicity by the accumulation of DNA oxidative damage. Brusatol, a potent NRF2 inhibitor, showed a promising effect in suppressing SDHBKD metastatic lesions in vivo, with prolonged overall survival in mice bearing PCPG allografts. Our findings highlight a novel therapeutic strategy of targeting the NRF2-driven glutathione metabolic pathway against SDHB-mutated PCPG.
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