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

Publication ,  Journal Article
Ravi, D; Beheshti, A; Abermil, N; Lansigan, F; Kinlaw, W; Matthan, NR; Mokhtar, M; Passero, FC; Puliti, P; David, KA; Dolnikowski, GG; Su, X ...
Published in: Front Oncol
2021

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.

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Published In

Front Oncol

DOI

ISSN

2234-943X

Publication Date

2021

Volume

11

Start / End Page

725137

Location

Switzerland

Related Subject Headings

  • 3211 Oncology and carcinogenesis
  • 3202 Clinical sciences
  • 1112 Oncology and Carcinogenesis
 

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Ravi, D., Beheshti, A., Abermil, N., Lansigan, F., Kinlaw, W., Matthan, N. R., … Evens, A. M. (2021). Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma. Front Oncol, 11, 725137. https://doi.org/10.3389/fonc.2021.725137
Ravi, Dashnamoorthy, Afshin Beheshti, Nasséra Abermil, Frederick Lansigan, William Kinlaw, Nirupa R. Matthan, Maisarah Mokhtar, et al. “Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma.Front Oncol 11 (2021): 725137. https://doi.org/10.3389/fonc.2021.725137.
Ravi D, Beheshti A, Abermil N, Lansigan F, Kinlaw W, Matthan NR, et al. Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma. Front Oncol. 2021;11:725137.
Ravi, Dashnamoorthy, et al. “Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma.Front Oncol, vol. 11, 2021, p. 725137. Pubmed, doi:10.3389/fonc.2021.725137.
Ravi D, Beheshti A, Abermil N, Lansigan F, Kinlaw W, Matthan NR, Mokhtar M, Passero FC, Puliti P, David KA, Dolnikowski GG, Su X, Chen Y, Bijan M, Varshney RR, Kim B, Dave SS, Rudolph MC, Evens AM. Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma. Front Oncol. 2021;11:725137.

Published In

Front Oncol

DOI

ISSN

2234-943X

Publication Date

2021

Volume

11

Start / End Page

725137

Location

Switzerland

Related Subject Headings

  • 3211 Oncology and carcinogenesis
  • 3202 Clinical sciences
  • 1112 Oncology and Carcinogenesis