ECE2020 Oral Communications Adrenal and Cardiovascular Endocrinology (7 abstracts)
Inhibition of glutaminases as a potential novel treatment for SDHB-associated pheochromocytomas/paragangliomas
Balázs Sarkadi 1,2 , Meszaros Katalin 1,2,3 , Ildiko Krencz 4 , Letizia Canu 5 , Lilla Krokker 1 , Sara Zakarias 6 , Gabor Barna 4 , Anna Sebestyen 3,4 , Judit Papay 4 , Zoltan Hujber 4 , Henriett Butz 1,2,3,7 , Otto Darvasi 2,3 , Peter Igaz 6,8 , Judit Doczi 9 , Michaela Luconi 5 , Christos Chinopoulos 9 & Attila Patocs 1,2,3,7
1Semmelweis University, Endocrine Genetics Laboratory, Budapest, Hungary; 2Hungarian Academy of Sciences and Semmelweis University, Hereditary Tumours Research Group, Budapest, Hungary; 3Bionics Innovation Center, Budapest, Hungary; 41st Department of Pathology and Experimental Cancer, Semmelweis University, Budapest, Hungary; 5University of Florence, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Florence, Italy; 6Semmelweis University, 2nd Department of Internal Medicine, Budapest, Hungary; 7National Institute of Oncology, Department of Molecular Genetics, Budapest, Hungary; 8Hungarian Academy of Sciences and Semmelweis University, Molecular Medicine Research Group, Budapest, Hungary; 9Semmelweis University, Department of Medical Biochemistry, Budapest, Hungary
Pheochromocytoma/paragangliomas (Pheo/PGL) are rare neuroendocrine cancers with strong genetic background. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) predispose to malignant disease with limited therapeutic options and poor prognosis. Novel prognostic markers and therapeutic targets are required to decrease the high mortality rate. Glutaminases play a crucial role in the metabolism of SDH impaired tumor cells. By using a host of cellular and molecular biology techniques in 2D and 3D cell culture formats we show that the proliferation of rat Pheo cell line PC12 is not affected negatively by the inhibition of SDH either by siRNA directed against SDHB or treatment with SDH inhibitors (itaconate and atpenin A5). BPTES, a specific glutaminase-1 (GLS1) inhibitor successfully decreased proliferation of SDH impaired PC12 cells. BPTES also significantly increased the ratio of dead cells in the 3D model of SDH impaired PC12 cell line. The role of GLS1 was assessed in 35 Pheo/PGL tumor tissues. Higher GLS1 expression was associated with lower SDHB expression. In summary, our data suggest that the SDH-associated malignant potential of Pheo/PGL is strongly dependent on GLS-1 expression and glutaminases may serve as novel prognostic and therapeutic targets.
Volume 70
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