Abstract
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.
Highlights
Pheochromocytomas and paragangliomas (PCPGs) are neuroendocrine tumors derived from chromaffin cells, which are commonly located in adrenal and extra-adrenal compartments
Cancer-associated SDHB mutations have been found to result in the functional disruption of mitochondrial complex II, which causes catastrophic changes to cellular metabolism and redox homeostasis [25,26,27,28]
pheochromocytomas and paragangliomas (PCPGs), we established SDHBKD PCPG cell lines based on the mouse pheochromocytoma cell line MPC
Summary
Pheochromocytomas and paragangliomas (PCPGs) are neuroendocrine tumors derived from chromaffin cells, which are commonly located in adrenal and extra-adrenal compartments. PCPG tumorigenesis is related to genetic alterations in 21 genes, which cluster into three major molecular subtypes on the basis of their signature transcriptomic profiles [1,2,3]. Cluster I PCPGs are characterized by the activation of the pseudohypoxia-related signaling pathway, which includes mutations in hypoxia-inducible factor 2A (HIF2A), succinate dehydrogenase subunits (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2), von Hippel–Lindau tumor suppressor (VHL), egl-9 prolyl hydroxylases 1 and 2 (EGLN1/2), fumarate hydratase (FH), malate dehydrogenase 2 (MDH2), and the ATP-dependent helicase (ATRX). Cluster III PCPGs are a recently identified disease subtype, with a transcriptomic signature of Wnt/β-catenin signaling [8]. Among all molecular subtypes of PCPGs, genetic abnormalities in SDHx underlie the most aggressive phenotype, with a strong tendency to metastatic disease, tumor multiplicity, and recurrence [11,12,13,14]
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