Work

Demethylzeylasteral inhibits oxidative phosphorylation complex biogenesis by targeting LRPPRC in lung cancer

Year: 2024

Type: article

Abstract: Targeted inhibition of mitochondrial oxidative phosphorylation (OXPHOS) complex generation is an emerging and promising cancer treatment strategy, but limited targets and specific inhibitors have been reported.Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is an atypical RNA-binding protein that regulates the stability of all 13 mitochondrial DNA-encoded mRNA (mt-mRNA) and thus participates in the synthesis of the OXPHOS complex.LRPPRC is also a prospective therapeutic target for lung adenocarcinoma, serving as a promising target for OXPHOS inhibition.In this study, we identified Demethylzeylasteral (T-96), a small molecule extracted from the Chinese herb Tripterygium wilfordii Hook.f., as a novel inhibitor of LRPPRC.T-96 directly bound to the RNA-binding domain of LRPPRC, inhibiting its interaction with mt-mRNA.This led to instability in both mt-mRNA and LRPPRC protein.Treatment with T-96 significantly reduced the mRNA and protein levels of the OXPHOS complex.As a consequence of LRPPRC inhibition, T-96 treatment induced a defect in the synthesis of the OXPHOS complex, inhibiting mitochondrial aerobic respiration and ATP synthesis.Moreover, T-96 exhibited potent antitumor activity for lung adenocarcinoma in vitro and in vivo, and the antitumor effect of T-96 was dependent on LRPPRC expression.In conclusion, this study not only identified the first traditional Chinese medicine monomer inhibitor against OXPHOS complex biosynthesis as well as a novel target of Demethylzeylasteral, but also shed light on the unique antitumor mechanism of bioactive compounds derived from traditional Chinese medicine.

Source: Journal of Cancer

DOI: 10.7150/jca.92797