title: NF-κB inhibition significantly upregulates the norepinephrine transporter system, causes apoptosis in pheochromocytoma cell lines and prevents metastasis in an animal model.
abstract: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are specific types of neuroendocrine tumors that originate in the adrenal medulla or sympathetic/parasympathetic paraganglia, respectively. Although these tumors are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in this study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on the cell membrane norepinephrine transporter (NET) system, considered to be the gatekeeper for the radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG). We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was performed on three different stable PHEO cell lines. We found that blocking NF-κB with TTL or capsaicin increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, in vivo treatment with TTL significantly reduced metastatic burden in an animal model of metastatic PHEO. The present study for the first time shows how NF-κB inhibitors could be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis.
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. karel@mail.nih.gov
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Marta
authors.initials: M
authors.lastname: Sirova
authors.forename: Alessio
authors.initials: A
authors.lastname: Giubellino
authors.forename: Lubomira
authors.initials: L
authors.lastname: Lencesova
authors.forename: Lucia
authors.initials: L
authors.lastname: Csaderova
authors.forename: Marcela
authors.initials: M
authors.lastname: Laukova
authors.forename: Sona
authors.initials: S
authors.lastname: Hudecova
authors.forename: Olga
authors.initials: O
authors.lastname: Krizanova
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D009362:Neoplasm Metastasis; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010235:Paraganglioma / Q000378:metabolism; D010616:Phenanthrenes / Q000008:administration & dosage / Q000494:pharmacology; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D034622:RNA Interference; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D016328:NF-kappa B; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010616:Phenanthrenes; C001899:triptolide