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Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma
Y. Pang, Y. Lu, V. Caisova, Y. Liu, P. Bullova, TT. Huynh, Y. Zhou, D. Yu, Z. Frysak, I. Hartmann, D. Taïeb, K. Pacak, C. Yang,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural
NLK
Free Medical Journals
od 1995 do Před 1 rokem
Freely Accessible Science Journals
od 1995
Open Access Digital Library
od 1995-01-01
Open Access Digital Library
od 1995-01-01
- 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
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.
Citace poskytuje Crossref.org
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