Glutaminases as a Novel Target for SDHB-Associated Pheochromocytomas/Paragangliomas

Abstract

Pheochromocytoma/paragangliomas (Pheo/PGL) are rare endocrine cancers with strong genetic background. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) predispose patients to malignant disease with limited therapeutic options and poor prognosis. Using a host of cellular and molecular biology techniques in 2D and 3D cell culture formats we show that SDH inhibition had cell line specific biological and biochemical consequences. Based on our studies performed on PC12 (rat chromaffin cell line), Hela (human cervix epithelial cell line), and H295R (human adrenocortical cell line) cells, we demonstrated that chromaffin cells were not affected negatively by the inhibition of SDH either by siRNA directed against SDHB or treatment with SDH inhibitors (itaconate and atpenin A5). Cell viability and intracellular metabolite measurements pointed to the cell line specific consequences of SDH impairment and to the importance of glutamate metabolism in chromaffin cells. A significant increase in glutaminase-1 (GLS-1) expression after SDH impairment was observed in PC12 cells. GLS-1 inhibitor BPTES was capable of significantly decreasing proliferation of SDH impaired PC12 cells. Glutaminase-1 and SDHB expressions were tested in 35 Pheo/PGL tumor tissues. Expression of GLS1 was higher in the SDHB low expressed group compared to SDHB high expressed tumors. Our data suggest that the SDH-associated malignant potential of Pheo/PGL is strongly dependent on GLS-1 expression and glutaminases may be novel targets for therapy.

Three Dimensional Cell Culturing for Modeling Adrenal and Pituitary Tumors

“…further supporting that this model can be successfully used in evaluation of novel therapeutical option in this disease [9].…”

“…Interestingly, in several tumor types 3D models have been introduced into research modalities however they are lacking regarding endocrine tumor types. To date, four of each adrenocortical carcinoma, pituitary neuroendocrine tumor (pitNET) and pheochromocytoma [9][10][11][12][13][14][15][16][17][18][19][20] reports have been published using 3D cultures, they are different in terms of the applied methods and no viability and lifespan analysis have been tested and compared among different culture conditions. Therefore, in the use of 3D culturing in routine research applications the methodology should be optimized and standardized in order to maintain viability observed in vivo systems.…”

Seven Novel Genes Related to Cell Proliferation and Migration of VHL-Mutated Pheochromocytoma

“…Nowadays, more and more attention had been paid to the targeted therapy of PPGL ( 50 ). Therefore, optimizing the diagnostic efficiency of metastatic PPGL and finding more effective biological target molecules had gradually become the trend of clinical and basic research ( 51 ). In this study, the most relevant tumor malignant indicators and essential biological characteristics were used as screening criteria, and high-throughput technology was used to comprehensively evaluate the molecular mechanism of tumor pathogenesis.…”

Hypoxia Signaling in Cancer: From Basics to Clinical Practice

“…lipid metabolic alterations or autophagy). Even certain oncogenic mutations result in oncometabolite production [ 40 ]. Tumor growth induces activation of several additional early or late stress responses i.e.…”