Biology subjects

Bonglack, E. N.

Publications and source records attributed to Bonglack, E. N..

2 recordsLinked to original sources

bioRxiv2024

Fatty acid desaturases link cell metabolism pathways to promote proliferation of Epstein-Barr virus-infected B cells

Epstein-Barr virus (EBV) is a gamma herpesvirus that infects up to 95% of the human population by adulthood, typically remaining latent in the host memory B cell pool. In immunocompromised individuals, EBV can drive the transformation and rapid proliferation of infected B cells, ultimately resulting in neoplasia. The same transformation process can be induced in vitro, with EBV-infected peripheral blood mononuclear cells (PBMCs) forming immortalized lymphoblastoid cell lines (LCLs) within weeks. In this study, we found that the fatty acid desaturases stearoyl-CoA desaturase 1 (SCD1) and fatty acid desaturase 2 (FADS2) are upregulated by EBV, and crucial for EBV-induced B cell proliferation. Additionally, we found that pharmacological and genetic inhibition of both SCD1 and FADS2 results in a significantly greater reduction in proliferation and cell cycle arrest, compared to perturbing either enzyme individually. Additionally, we found that inhibiting either SCD1 or FADS2 alone hypersensitizes LCLs to palmitate-induced apoptosis, recapitulating studies in other tissue types. Further lipidomic and metabolic analysis of dual SCD1/FADS2-inhibited LCLs revealed an increase in free unsaturated fatty acids, a reduction of oxidative phosphorylation, and a reduction of glycolysis, thereby linking the activity of SCD1 and FADS2 to overall growth-promoting metabolism. Lastly, we show that SCD1 and FADS2 are important in the growth of clinically derived EBV+ immunoblastic lymphoma cells. Collectively, these data demonstrate a previously uncharacterized role of lipid desaturation in EBV+ transformed B cell proliferation, revealing a metabolic pathway that can be targeted in future anti-lymphoma therapies.

microbiology↗

bioRxiv2020

Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas

Epstein-Barr Virus (EBV) is a ubiquitous herpesvirus that typically causes asymptomatic infection but can promote B lymphoid tumors in the immune-suppressed. In vitro, EBV infection of primary B cells stimulates glycolysis during immortalization into lymphoblastoid cell lines (LCLs). Lactate export during glycolysis is crucial for continued proliferation of many cancer cells-part of a phenomenon known as the "Warburg effect," and is mediated by the monocarboxylate transporters 1 and 4 (MCT1 and MCT4). However, the role of MCT1/4 has yet to be studied in EBV-associated malignancies which display Warburg-like metabolism in vitro. Here, we show that EBV infection of B lymphocytes directly promotes temporal induction of MCT1 and MCT4 through the viral proteins EBNA2 and LMP1 respectively, with MCT1 being induced early after infection and MCT4 late. Remarkably, singular MCT1 inhibition early, and dual MCT1/4 inhibition in LCLs using a novel MCT4-selective inhibitor led to growth arrest and lactate buildup. Metabolic profiling in LCLs revealed significatly reduced oxygen consumption rates (OCR) and NAD+/NADH ratios, contrary to prevous observations of increased OCR and unaltered NAD+/NADH ratios in MCT1/MCT4-inhibited cancer cells. Furthermore, U-13C6 glucose labeling of MCT1/4-inhibited LCLs also revealed increased labeling of glutathione in the presence of elevated ROS and depleted glutathione pools, as well as increased labeling of de novo pyrimidine biosynthetic intermediates, suggesting broad effects on LCL metabolism. These vulnerabilities sensitized LCLs as well as EBV+, and the related gammaherpesvirus KSHV+ lymphoma cell lines to killing by metformin and phenformin, pointing at a novel therapeutic approach for viral lymphomas.

cancer biology↗