OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro and animal laboratory research
PubMed 39862868 · doi:10.1016/j.molcel.2024.12.025
What was done
The authors investigated the regulatory mechanisms controlling 3-oxoacid CoA-transferase 1 (OXCT1) and ketolysis in hepatocellular carcinoma (HCC). They used HCC cell lines and mouse models to examine the biochemical interaction between OXCT1 and SUCLA2 following IGF1 stimulation, delineating the upstream signaling pathway (ERK2 and PIN1) and downstream succinylation of OXCT1 at K421. They evaluated tumor growth and assessed the therapeutic effect of the OXCT1 inhibitor acetohydroxamic acid alone and combined with lenvatinib in mice.
What was found
The abstract reports no numerical values, effect sizes, or p-values. Mechanistically, IGF1 stimulation led to ERK2-mediated phosphorylation of SUCLA2 at S124 and PIN1-mediated isomerization, promoting SUCLA2-OXCT1 binding. SUCLA2-derived succinyl-CoA directly succinylated OXCT1 at K421, activating it and increasing ketolysis, HCC proliferation, and mouse tumor growth. Pharmacological inhibition of OXCT1 with acetohydroxamic acid suppressed liver tumor growth and enhanced lenvatinib response in mice.
Why it matters
This study identifies an IGF1-ERK2-PIN1-SUCLA2-OXCT1 regulatory cascade driving metabolic reprogramming via ketolysis in liver cancer. It provides a preclinical rationale for targeting OXCT1 by repurposing the existing drug acetohydroxamic acid to augment lenvatinib therapy.
Limits
The abstract does not disclose sample sizes, quantitative metrics, or statistical values. Findings are entirely preclinical, derived from cultured cells and animal models, and have not been validated for safety or efficacy in human clinical trials.
Cited by
- supports Certain types of cancer cells can utilize ketone bodies and accelerate their growth in response to them.