title: Role of microenvironment on neuroblastoma SK-N-AS SDHB-silenced cell metabolism and function.
abstract: In solid tumors, neoplastic cells grow in contact with the so-called tumor microenvironment. The interaction between tumor cells and the microenvironment causes reciprocal metabolic reprogramming and favorable conditions for tumor growth and metastatic spread. To obtain an experimental model resembling the in vivo conditions of the succinate dehydrogenase B subunit (SDHB)-mutated paragangliomas (PGLs), we evaluated the effects of SDHB silencing on metabolism and proliferation in the human neuroblastoma cell line (SK-N-AS), cultured alone or in association with human fibroblasts. Silencing caused a 70% decrease in protein expression, an almost complete loss of the complex specific enzymatic activity, and a significant increase in HIF1α and HIF2α expression; it thus resembled the in vivo tumor cell phenotype. When compared with WT SK-N-AS cells, SDHB-silenced cells showed an altered metabolism characterized by an unexpected significant decrease in glucose uptake and an increase in lactate uptake. Moreover, silenced cells exhibited a significant increase in cell proliferation and metalloproteinase activity. When co-cultured with human fibroblasts, control cells displayed a significant decrease in glucose uptake and a significant increase in cell proliferation as compared with their mono-cultured counterparts. These effects were even more evident in co-cultured silenced cells, with a 70% decrease in glucose uptake and a 92% increase in cell proliferation as compared to their mono-cultured counterparts. The present data indicate for the first time, to our knowledge, that SDHB impairment causes metabolic and functional derangement of neural-crest-derived tumor cells and that the microenvironment, here represented by fibroblasts, strongly affects their tumor metabolism and growth capacity.
authors: Endocrinology UnitBiochemistry UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Hospital Carl Gustav Carus, Technische Universität, Dresden, GermanyIstituto Toscano TumoriFlorence, Italy.
authors: Elena
authors: E
authors: Rapizzi
authors: Endocrinology UnitBiochemistry UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Hospital Carl Gustav Carus, Technische Universität, Dresden, GermanyIstituto Toscano TumoriFlorence, Italy.
authors: Rossella
authors: R
authors: Fucci
authors: Endocrinology UnitBiochemistry UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Hospital Carl Gustav Carus, Technische Universität, Dresden, GermanyIstituto Toscano TumoriFlorence, Italy.
authors: Elisa
authors: E
authors: Giannoni
authors: Endocrinology UnitBiochemistry UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Hospital Carl Gustav Carus, Technische Universität, Dresden, GermanyIstituto Toscano TumoriFlorence, Italy.
authors: Letizia
authors: L
authors: Canu
authors: Endocrinology UnitBiochemistry UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Hospital Carl Gustav Carus, Technische Universität, Dresden, GermanyIstituto Toscano TumoriFlorence, Italy.
authors: Susan
authors: S
authors: Richter
authors: Endocrinology UnitBiochemistry UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Hospital Carl Gustav Carus, Technische Universität, Dresden, GermanyIstituto Toscano TumoriFlorence, Italy.
authors: Paolo
authors: P
authors: Cirri
authors: Endocrinology UnitBiochemistry UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Hospital Carl Gustav Carus, Technische Universität, Dresden, GermanyIstituto Toscano TumoriFlorence, Italy Endocrinology UnitBiochemistry UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Hospital Carl Gustav Carus, Technische Universität, Dresden, GermanyIstituto Toscano TumoriFlorence, Italy massimo.mannelli@unifi.it.
authors: Massimo
authors: M
authors: Mannelli
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010235:Paraganglioma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010673:Pheochromocytoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D059016:Tumor Microenvironment
chemical_list: C491545:SDHD protein, human; D013385:Succinate Dehydrogenase
keywords: SDHB; fibroblast; glucose/lactate; pheochromocytoma/paraganglioma; tumor microenvironment