A Mechanistic Investigation of Serine Hydroxymethyltransferase Inhibition in Lymphoma and Leukemia Cell Lines

Abstract

Cancer cells demonstrate unusually high rates of cell growth and proliferation, for which they require upregulated rates of one-carbon (1C) metabolism. The folate cycle is crucial for providing 1C units to the cell. Subsequently, many enzymes involved in the folate cycle have been noted for their upregulation in cancer cells, including serine hydroxymethyl transferase (SHMT), which converts serine and tetrahydrofolate (THF) to glycine and 5,10-methylene-THF (5,10-meTHF), respectively. A novel inhibitor of SHMT, Serine Hydroxymethyltransferase Inhibitor 1 (SHIN1), was developed by the Rabinowitz Lab. SHIN1 has shown potency in a variety of different cancer cell lines, but shows particular potency in diffuse large B-cell lymphoma (DLBCL) cell lines. In this work, a greater understanding of the mechanistic effects of SHIN1 in both lymphoma and leukemia cell lines was established through the use of isotopic labeling experiments, analysis of metabolites using liquid chromatography-mass spectrometry (LC-MS), and detection of apoptosis using flow cytometry. It was found that SHIN1 leads to a depletion of purines in lymphoma and leukemia cell lines, as well as inducing apoptosis. Upon co-treating DLBCL cell lines with both SHIN1 and an additional source of purines, the growth inhibition, apoptotic effects, and metabolic phenotypes seen under SHIN1 inhibition were reversed. This work allows for a greater understanding of the effect of the compound on cells, allowing for the potential for development of an alternative therapy for DLBCL patients who do not respond to conventional therapy.