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Demethylzeylasteral inhibits oxidative phosphorylation complex biogenesis by targeting LRPPRC in lung cancer
Lina Wang1,2, Wei Zhou3, Wenxi Wang3
1Key Laboratory of Molecular Nanostructure and Nanotechnology, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Science, Beijing 100190, PR China.
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.
Insights
Demethylzeylasteral (T-96), derived from Chinese herbs, inhibits LRPPRC, a key protein in mitochondrial complex synthesis. This novel approach shows potent antitumor effects against lung adenocarcinoma by disrupting oxidative phosphorylation.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeted inhibition of mitochondrial oxidative phosphorylation (OXPHOS) complex generation is a promising cancer treatment strategy.
- Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is crucial for mitochondrial DNA-encoded mRNA stability and OXPHOS complex synthesis.
- LRPPRC is a potential therapeutic target for lung adenocarcinoma, offering a route for OXPHOS inhibition.
Purpose of the Study:
- To identify novel inhibitors of LRPPRC for cancer treatment.
- To investigate the potential of Demethylzeylasteral (T-96) as an LRPPRC inhibitor.
- To elucidate the antitumor mechanism of T-96 in lung adenocarcinoma.
Main Methods:
- Identified Demethylzeylasteral (T-96) from Tripterygium wilfordii Hook. f. as an LRPPRC inhibitor.
- Assessed T-96's direct binding to LRPPRC's RNA-binding domain and its effect on mt-mRNA interaction.
- Evaluated T-96's impact on mt-mRNA and LRPPRC protein stability, OXPHOS complex levels, mitochondrial respiration, ATP synthesis, and antitumor activity in vitro and in vivo.
Main Results:
- T-96 directly binds to LRPPRC, inhibiting its interaction with mt-mRNA and leading to reduced mt-mRNA and LRPPRC protein stability.
- T-96 treatment significantly decreased OXPHOS complex mRNA and protein levels, impaired mitochondrial aerobic respiration and ATP synthesis.
- T-96 demonstrated potent in vitro and in vivo antitumor activity against lung adenocarcinoma, with efficacy dependent on LRPPRC expression.
Conclusions:
- Demethylzeylasteral (T-96) is the first identified traditional Chinese medicine monomer inhibitor targeting OXPHOS complex biosynthesis via LRPPRC inhibition.
- T-96 represents a novel therapeutic agent for lung adenocarcinoma, acting through the disruption of mitochondrial function.
- This study highlights the potential of bioactive compounds from traditional Chinese medicine in developing novel cancer therapies.
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