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HJC0152 suppresses human non-small-cell lung cancer by inhibiting STAT3 and modulating metabolism
1Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Objectives:
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and overexpressed in many cancers, including non-small-cell lung cancer (NSCLC). We recently developed HJC0152 as an orally active STAT3 inhibitor. This study focused on investigating HJC0152's effect and mechanism of action in NSCLC.
Materials And Methods:
We analysed cell proliferation by MTT assays, cell migration by wound healing and transwell assays, protein levels by Western blot, and apoptosis and reactive oxygen species (ROS) level by flow cytometry. A nude mouse tumorigenesis model was established for in vivo experiment. UHPLC-QTOF/MS was used for untargeted metabolomic relative quantitation analysis.
Results:
We found that HJC0152 exhibited activity against human NSCLC cells in vitro and NSCLC xenograft tumours in vivo via regulating STAT3 signalling and metabolism. HJC0152 efficiently reduced NSCLC cell proliferation, promoted ROS generation, induced apoptosis, triggered DNA damage and reduced motility in A549 and H460 NSCLC cells. Moreover, HJC0152 significantly inhibited the growth of A549 xenograft tumours in vivo. HJC0152 also affected metabolism, significantly decreasing and perturbating levels of several metabolites in the purine, glutathione and pyrimidine metabolism pathways.
Conclusions:
HJC0152 reduces cellular capacity to scavenge free radicals, leading to ROS generation and accumulation and apoptosis. This study provides a rationale for further developing HJC0152 as a potential therapy for NSCLC and provides insights into the mechanisms by which HJC0152 exerts its anti-cancer effects.
Insights
HJC0152, an oral STAT3 inhibitor, effectively reduced non-small-cell lung cancer (NSCLC) cell proliferation and tumor growth. It induced apoptosis by increasing reactive oxygen species (ROS) and altering cancer metabolism.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Signal transducer and activator of transcription 3 (STAT3) is frequently activated in cancers like non-small-cell lung cancer (NSCLC).
- HJC0152 is an orally available inhibitor targeting STAT3, a key signaling pathway in cancer development.
Purpose of the Study:
- To investigate the anti-cancer effects and mechanisms of HJC0152 in non-small-cell lung cancer (NSCLC).
- To evaluate HJC0152's impact on STAT3 signaling, cellular metabolism, and tumor growth in NSCLC models.
Main Methods:
- In vitro assays: MTT for proliferation, wound healing/Transwell for migration, Western blot for protein, flow cytometry for apoptosis and ROS.
- In vivo studies: Nude mouse xenograft model for tumor growth inhibition.
- Metabolomic analysis: UHPLC-QTOF/MS for untargeted metabolic profiling.
Main Results:
- HJC0152 inhibited NSCLC cell proliferation, induced apoptosis, triggered DNA damage, and reduced motility in vitro.
- Significant reduction in A549 xenograft tumor growth was observed in vivo.
- HJC0152 altered purine, glutathione, and pyrimidine metabolism, decreasing key metabolites.
Conclusions:
- HJC0152 enhances reactive oxygen species (ROS) generation, leading to apoptosis and reduced cancer cell viability.
- The study supports HJC0152 as a potential therapeutic agent for NSCLC, highlighting its multifaceted anti-cancer mechanisms.
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