| Title: |
Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma |
| Authors: |
Ravi, Dashnamoorthy; Beheshti, Afshin; Abermil, Nasséra; Lansigan, Frederick; Kinlaw, William; Matthan, Nirupa, R; Mokhtar, Maisarah; Passero, Frank, C; Puliti, Patrick; David, Kevin, A; Dolnikowski, Gregory, G; Su, Xiaoyang; Chen, Ying; Bijan, Mahboubi; Varshney, Rohan, R; Kim, Baek; Dave, Sandeep, S; Rudolph, Michael, C; Evens, Andrew, M |
| Contributors: |
Rutgers cancer institute of New Jersey Newark, NJ; Rutgers University Newark; Rutgers University System (Rutgers); Massachusetts Institute of Technology (MIT); NASA Ames Research Center (ARC); CHU Saint-Antoine AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Geisel School of Medicine at Dartmouth; Tufts University School of Medicine Boston; University of Rochester Medical Center (URMC); Emory University School of Medicine; Emory University Atlanta, GA; University of Oklahoma (OU); Children’s Healthcare of Atlanta; Duke University Medical Center |
| Source: |
ISSN: 2234-943X ; Frontiers in Oncology ; https://hal.sorbonne-universite.fr/hal-03429313 ; Frontiers in Oncology, 2021, 11, ⟨10.3389/fonc.2021.725137⟩. |
| Publisher Information: |
CCSD; Frontiers Media |
| Publication Year: |
2021 |
| Subject Terms: |
lipid metabolism; pentose phosphate pathway; nucleotides; metabolomics; FASN; non-Hodgkin lymphoma; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.3389/fonc.2021.725137 |
| Availability: |
https://hal.sorbonne-universite.fr/hal-03429313; https://hal.sorbonne-universite.fr/hal-03429313v1/document; https://hal.sorbonne-universite.fr/hal-03429313v1/file/fonc-11-725137.pdf; https://doi.org/10.3389/fonc.2021.725137 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.439E879D |
| Database: |
BASE |