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Sculponeatin A induces mitochondrial dysfunction in non-small cell lung cancer through WWP2-mediated degradation of
Fang Wan1, Chen Qian1, Xuewen Liu1,2
1Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.
Background And Purpose:
The phosphorylation of signal transducer and activator of transcription 3 (STAT3) monomer at S727 promotes its mitochondrial localisation and regulates mitochondrial function, thus exerting a protective effect on tumour cells. However, no inhibitor drugs targeting mitochondrial STAT3 (mitoSTAT3) or S727-STAT3 phosphorylation have been identified. Here, we report a novel diterpenoid extracted from Isodon sculponeatus, sculponeatin A (sptA), induces mitochondrial dysfunction in non-small cell lung cancer (NSCLC) by targeting mitoSTAT3 degradation.
Experimental Approach:
xCELLigence real-time cell analysis assay and high-content analysis were performed to measure cytotoxicity. Mitochondrial function was assessed by transmission electron microscopy, mitochondrial permeability transition pore opening and Seahorse cellular flux assays. The effects of sptA on the upstream signalling pathway of mitochondrial dysfunction were measured by Western blot, gene alterations and other approaches. Immunofluorescence and live cell imaging were performed to visualise the expression and position of mitoSTAT3. Nude mice and zebrafish were modelled with subcutaneous xenografts. Pharmacokinetics of sptA were examined in rats. Drug toxicity was evaluated in zebrafish.
Key Results:
sptA inhibited mitochondrial respiration in NSCLC cells. sptA induced mitochondrial dysfunction by promoting the degradation of mitoSTAT3. sptA promoted WW domain containing E3 ubiquitin protein ligase 2 (WWP2)-mediated ubiquitination and degradation of mitoSTAT3 through direct binding. sptA inhibited tumour growth in vivo. Evaluation of drug toxicity in zebrafish showed that overdose of sptA may cause heart damage.
Conclusions And Implications:
These findings suggest that pharmacological targeting the degradation of mitoSTAT3 by sptA may provide therapeutic benefits against NSCLC.
Insights
A novel compound, sculponeatin A (sptA), targets mitochondrial STAT3 (mitoSTAT3) for degradation, inducing mitochondrial dysfunction and inhibiting non-small cell lung cancer (NSCLC) growth. This discovery offers a new therapeutic strategy for NSCLC by targeting mitoSTAT3 degradation.
Area of Science:
- Mitochondrial biology
- Cancer research
- Pharmacology
Background:
- Signal transducer and activator of transcription 3 (STAT3) phosphorylation at S727 promotes mitochondrial localization and tumor cell protection.
- No inhibitors targeting mitochondrial STAT3 (mitoSTAT3) or S727-STAT3 phosphorylation are currently available.
- Mitochondrial STAT3 plays a role in regulating mitochondrial function and tumor cell survival.
Purpose of the Study:
- To identify novel therapeutic agents targeting mitochondrial STAT3 (mitoSTAT3) in non-small cell lung cancer (NSCLC).
- To investigate the mechanism of action of sculponeatin A (sptA), a diterpenoid from Isodon sculponeatus, in NSCLC.
- To evaluate the potential of targeting mitoSTAT3 degradation for NSCLC treatment.
Main Methods:
- Real-time cell analysis (xCELLigence) and high-content analysis for cytotoxicity.
- Assessment of mitochondrial function using transmission electron microscopy, mitochondrial permeability transition pore opening, and Seahorse cellular flux assays.
- Western blot, gene alteration analysis, immunofluorescence, and live cell imaging to study signaling pathways and protein localization.
- In vivo studies using nude mouse xenografts and zebrafish models.
- Pharmacokinetic and toxicity evaluations in rats and zebrafish.
Main Results:
- Sculponeatin A (sptA) inhibited mitochondrial respiration in NSCLC cells.
- sptA induced mitochondrial dysfunction by promoting the ubiquitination and degradation of mitoSTAT3 via WWP2.
- sptA demonstrated anti-tumor activity in vivo, inhibiting tumor growth.
- Zebrafish toxicity studies indicated potential heart damage at overdose levels.
Conclusions:
- Sculponeatin A (sptA) effectively targets mitoSTAT3 for degradation, leading to mitochondrial dysfunction and anti-cancer effects in NSCLC.
- Targeting mitoSTAT3 degradation represents a promising therapeutic strategy for NSCLC.
- Further research into sptA's efficacy and safety profile is warranted for clinical application.
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