Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma

Dashnamoorthy Ravi; Afshin Beheshti; Nasséra Abermil; Frederick Lansigan; William Kinlaw; Nirupa R Matthan; Maisarah Mokhtar; Frank C Passero Jr; Patrick Puliti; Kevin A David; Gregory G Dolnikowski; Xiaoyang Su; Ying Chen; Mahboubi Bijan; Rohan R Varshney; Baek Kim; Sandeep S Dave; Michael C Rudolph; Andrew M Evens

doi:10.3389/fonc.2021.725137

Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma

Front Oncol. 2021 Oct 26:11:725137. doi: 10.3389/fonc.2021.725137. eCollection 2021.

Authors

Dashnamoorthy Ravi^{1

2}, Afshin Beheshti^{3

4}, Nasséra Abermil⁵, Frederick Lansigan^{6

7}, William Kinlaw⁸, Nirupa R Matthan⁹, Maisarah Mokhtar¹, Frank C Passero Jr¹⁰, Patrick Puliti^{1

6

7}, Kevin A David^{1

2}, Gregory G Dolnikowski⁹, Xiaoyang Su^{2

11}, Ying Chen¹², Mahboubi Bijan¹³, Rohan R Varshney¹⁴, Baek Kim^{13

15}, Sandeep S Dave¹⁶, Michael C Rudolph¹⁴, Andrew M Evens^{1

2}

Affiliations

¹ Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.
² Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States.
³ Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, United States.
⁴ KBR, Space Biosciences Division, National Aeronautical and Space Administration, Ames Research Center, Moffett Field, CA, United States.
⁵ Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Service d'Hématologie Biologique, Paris, France.
⁶ Department of Medicine, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States.
⁷ Department of Medicine, Section of Endocrinology and Metabolism, Geisel School of Medicine at Dartmouth, Hanover, NH, United States.
⁸ Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States.
⁹ Jean Mayer United States Department of Agriculture (USDA) Human Nutrition Research Center on Aging, Tufts University, Boston, MA, United States.
¹⁰ Department of Medicine, University of Rochester Medical Center, Rochester, NY, United States.
¹¹ Metabolomics Core, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.
¹² Bioinformatics Core, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.
¹³ Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, United States.
¹⁴ Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, Oklahoma, OK, United States.
¹⁵ Center for Drug Discovery, Children's Healthcare of Atlanta, Atlanta, GA, United States.
¹⁶ Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States.

Abstract

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.

Keywords: FASN; lipid metabolism; metabolomics; non-Hodgkin lymphoma; nucleotides; pentose phosphate pathway.