Targeting NRF2-Governed Glutathione Synthesis for <i>SDHB</i>-Mutated Pheochromocytoma and Paraganglioma

• Main Authors: Yang Liu, Ying Pang, Veronika Caisova, Jianyi Ding, Di Yu, Yiqiang Zhou, Thanh-Truc Huynh, Hans Ghayee, Karel Pacak, Chunzhang Yang
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Cancers
• Subjects: nrf2; glutathione metabolism; sdhb mutation; pheochromocytoma; paraganglioma
• Online Access: https://www.mdpi.com/2072-6694/12/2/280

Succinate dehydrogenase subunit B (SDHB) deficiency frequently occurs in cluster I pheochromocytomas and paragangliomas (PCPGs). <i>SDHB</i>-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 <i>SDHB</i>-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 (<i>SDHB^KD</i>) cells. NRF2 blockade not only disrupted ROS homeostasis in <i>SDHB</i>-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 <i>SDHB^KD</i> 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 <i>SDHB</i>-mutated PCPG.