PUBLICATION
Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma
- Authors
- Anderson, N.M., Qin, X., Finan, J.M., Lam, A., Athoe, J., Missiaen, R., Skuli, N., Kennedy, A., Saini, A.S., Tao, T., Zhu, S., Nissim, I., Look, A.T., Qing, G., Simon, M.C., Feng, H.
- ID
- ZDB-PUB-210709-5
- Date
- 2021
- Source
- Cancer research 81(17): 4417-4430 (Journal)
- Registered Authors
- Feng, Hui, Look, A. Thomas, Tao, Ting, Zhu, Shizhen
- Keywords
- none
- MeSH Terms
-
- Acyltransferases/metabolism*
- Animals
- Apoptosis
- Brain Neoplasms/metabolism*
- Cell Line, Tumor
- Collagen/chemistry
- Disease Models, Animal
- Drug Combinations
- Female
- Gene Expression Profiling
- HEK293 Cells
- Humans
- Inhibitory Concentration 50
- Ketoglutarate Dehydrogenase Complex/metabolism
- Laminin/chemistry
- Mice
- Mice, Inbred BALB C
- Neoplasm Invasiveness
- Neoplasm Transplantation
- Neuroblastoma/metabolism*
- Oxidative Phosphorylation*
- Oxygen/metabolism
- Proteoglycans/chemistry
- RNA Interference
- Risk
- Smegmamorpha
- Treatment Outcome
- Tricarboxylic Acids/metabolism
- Zebrafish
- PubMed
- 34233924 Full text @ Cancer Res.
Citation
Anderson, N.M., Qin, X., Finan, J.M., Lam, A., Athoe, J., Missiaen, R., Skuli, N., Kennedy, A., Saini, A.S., Tao, T., Zhu, S., Nissim, I., Look, A.T., Qing, G., Simon, M.C., Feng, H. (2021) Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma. Cancer research. 81(17):4417-4430.
Abstract
High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in neuroblastoma patients. DLST is an E2 component of the a-ketoglutarate (a-KG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, a-KG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than a-KG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. Additionally, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping