Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate

Goncalves, Judith; Moog, Sophie; Morin, Aurélie; Gentric, Géraldine; Müller, Sebastian; Morrell, Alexander P.; Kľučková, Katarína; Stewart, Theodora J.; Andoniadou, Cynthia L.; Lussey-Lepoutre, Charlotte; Bénit, Paule; Thakker, Alpesh; Vettore, Lisa; Roberts, Jennie; Rodriguez, Raphaël; Mechta‐Grigoriou, Fatima; Gimenez‐Roqueplo, Anne‐Paule; Letouzé, Éric; Tennant, Daniel A.; Favier, Judith

doi:10.1158/0008-5472.can-20-2936

Cited by 35 publications

(38 citation statements)

References 68 publications

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“…Ultimately, these data do not resolve the role of HIF activation in SDHx tumors; however, our data, and those of others, indicate that the proposed mechanism of succinate-mediated PHD inhibition is incomplete. Additional events such as ROS accumulation ( Goncalves et al, 2021 ) and/or CNL-LOH may be necessary for acquisition of the pseudohypoxic phenotype late in the tumorigenic process.…”

Section: Discussionmentioning

confidence: 99%

“…We propose that during tumor progression metabolic reprogramming relieves the ascorbate-dependence, which in turn potentiates 2-OG enzyme inhibition. Indeed, it has recently been shown that ultra-high-dose ascorbate preferentially kills both SDHB cell lines ( Goncalves et al, 2021 ) and SDHB allografts ( Liu et al, 2020 ). Notably, the role of ascorbate in maintaining the viability of SDH-deficient chromaffin cells does not explain the increased risk of SDHx-associated renal cell carcinoma and gastrointestinal stromal tumor, where ascorbate levels are low and alternative mechanisms of remediating oxidative stress, perhaps via glutathione regulation, would be required.…”

Section: Discussionmentioning

confidence: 99%

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SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas

et al. 2022

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“…This demonstrates the role of SDH-produced ROS in genomic instability within mammalian cells [31]. Furthermore, Guzy et al found that SDHB inhibition (Hep3B human hepatoma cells, A549 human alveolar epithelium-derived tumor cells, and 143B human osteosarcoma cells) led to the accumulation of ROS [32], which was later confirmed by SDHB silencing in rat PHEO cells (PC12 cells) [33], mouse PHEO cells (MPC cells) [34,35], immortalized mouse chromaffin cells [36], and human hPheo1 cells [34,35]. Moreover, an increase in mitochondrial ROS production was observed in our model of the SDHB knock-out in human PHEO cell line (hPheo1, unpublished data).…”

Section: Ros In Pheo and Pglmentioning

confidence: 91%

“…This ultimately results in cell death in vitro and delays tumor growth in vivo [34]. Recently, dysregulation of iron homeostasis and ascorbate-induced accumulation of ROS resulting in cell death has been observed in SDHB-mutated immortalized chromaffin cells [36].…”

Section: Targeting Of Ros Production In Pheo and Pglmentioning

confidence: 99%

Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma

Vanova

Yang

Meuter

et al. 2021

Cancers

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Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PHEO/PGL susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode succinate dehydrogenase (SDH). Patients with SDH subunit B (SDHB)-mutated PHEO/PGL exhibit a higher likelihood of developing metastatic disease, which can be partially explained by the metabolic cell reprogramming and redox imbalance caused by the mutation. Reactive oxygen species (ROS) are highly reactive molecules involved in a multitude of important signaling pathways. A moderate level of ROS production can help regulate cellular physiology; however, an excessive level of oxidative stress can lead to tumorigenic processes including stimulation of growth factor-dependent pathways and the induction of genetic instability. Tumor cells effectively exploit antioxidant enzymes in order to protect themselves against harmful intracellular ROS accumulation, which highlights the essential balance between ROS production and scavenging. Exploiting ROS accumulation can be used as a possible therapeutic strategy in ROS-scavenging tumor cells. Here, we focus on the role of ROS production in PHEO and PGL, predominantly in SDHB-mutated cases. We discuss potential strategies and approaches to anticancer therapies by enhancing ROS production in these difficult-to-treat tumors.

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“…Thus, constitutive Nrf2 activation appears to be involved in the development and progression of various human cancers. Although the question of whether the Nrf2 pathway is activate or not in SDHB related tumors is interesting and debated [ 23 , 24 ], the Nrf2 pathway in in PCC/PGL is poorly convincing.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of Nrf2 and elevated glucose uptake in pheochromocytoma and paraganglioma with SDHB gene mutation

et al. 2022

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Background Pheochromocytomas (PCC) and paragangliomas (PGL) are catecholamine-producing neuroendocrine tumors. According to the World Health Organization Classification 2017, all PCC/PGL are considered to have malignant potential. There is growing evidence that PCC/PGL represent a metabolic disease that leads to aerobic glycolysis. Cellular energy metabolism involves both transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and succinate dehydrogenase (SDH) subtypes, but the association of these substances with PCC/PGL is largely unknown. Methods We investigated SDHB gene mutation and protein expressions for SDHB and Nrf2 in surgical specimens from 29 PCC/PGL. We also assessed preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy-glucose positron emission tomography and mRNA levels for Nrf2. Results Among 5 PCC/PGL with a PASS Score ≥ 4 or with a moderately to poorly differentiated type in the GAPP Score, 4 were metastatic and found to be SDHB mutants with homogeneous deletion of SDHB protein. SDHB mutants showed a higher expression of Nrf2 protein and a higher preoperative SUVmax than non-SDHB mutants with a PASS < 4 or a well-differentiated GAPP type. Furthermore, protein expression of Nrf2 was positively associated with preoperative SUVmax. The Nrf2 mRNA level positively correlated with malignant phenotype, higher expression for Nrf2 protein and SDHB gene mutant, but negatively correlated with expression for SDHB protein. There was also a positive correlation between Nrf2 mRNA level and SUVmax. Conclusion These results suggest that activation of Nrf2 and elevated metabolism play roles in PCC/PGL with malignant potential that have SDHB gene mutation and SDHB deficiency.

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Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate

Cited by 35 publications

References 68 publications

SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas

SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas

Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma

Increased expression of Nrf2 and elevated glucose uptake in pheochromocytoma and paraganglioma with SDHB gene mutation

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