Metabolic dysfunctions enabling increased
nucleotide biosynthesis are necessary for supporting malignant proliferation. Our investigations indicate that upregulation of
fatty acid synthase (FASN) and de novo lipogenesis, commonly observed in many
cancers, are associated with
nucleotide metabolic dysfunction in
lymphoma. The results from our experiments showed that
ribonucleotide and
deoxyribonucleotide pool depletion, suppression of global
RNA/
DNA synthesis, and cell cycle inhibition occurred in the presence of FASN inhibition. Subsequently, we observed that FASN inhibition caused metabolic blockade in the rate-limiting step of the oxidative branch of the pentose phosphate pathway (oxPPP) catalyzed by
phosphogluconate dehydrogenase (PGDH). Furthermore, we determined that FASN inhibitor treatment resulted in
NADPH accumulation and inhibition of PGDH
enzyme activity.
NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. Through cell-free
enzyme assays consisting of FASN and PGDH, we delineated that the PGDH-catalyzed ribulose-5-phosphate synthesis is enhanced in the presence of FASN and is suppressed by increasing concentrations of
NADPH. Additionally, we observed that FASN and PGDH were colocalized in the cytosol. The results from these experiments led us to conclude that
NADP-
NADPH turnover and the reciprocal stimulation of FASN and PGDH catalysis are involved in promoting oxPPP and
nucleotide biosynthesis in
lymphoma. Finally, a transcriptomic analysis of
non-Hodgkin's lymphoma (n = 624) revealed the increased expression of genes associated with metabolic functions interlinked with oxPPP, while the expression of genes participating in oxPPP remained unaltered. Together we conclude that FASN-PGDH enzymatic interactions are involved in enabling oxPPP and
nucleotide metabolic dysfunction in
lymphoma tumors.