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.

• Klíčová slova
• metastatic pheochromocytoma, paraganglioma, reactive oxygen species, succinate dehydrogenase,
• Publikační typ
• časopisecké články MeSH

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors.Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft.Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423-32. ©2018 AACR.

• MeSH
• apoptóza genetika   MeSH
• biologické modely MeSH
• buněčný cyklus genetika   MeSH
• chemorezistence genetika   MeSH
• cílená molekulární terapie MeSH
• feochromocytom farmakoterapie   genetika   metabolismus   patologie   MeSH
• lidé MeSH
• mitochondrie metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• myši MeSH
• NAD metabolismus   MeSH
• nádorové buněčné linie MeSH
• oprava DNA * MeSH
• paragangliom farmakoterapie   genetika   metabolismus   patologie   MeSH
• PARP inhibitory farmakologie   terapeutické užití   MeSH
• poly(ADP-ribosa)polymerasy metabolismus   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• signální transdukce účinky léků   MeSH
• sukcinátdehydrogenasa genetika   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• NAD MeSH
• PARP inhibitory MeSH
• poly(ADP-ribosa)polymerasy MeSH
• protinádorové látky MeSH
• SDHB protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH