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Published on: March 15, 2024
Echinatin suppresses cutaneous squamous cell carcinoma by targeting GSTM3-mediated ferroptosis
Ziwei Kang1, Peiru Wang1, Bo Wang2
1Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
Background:
Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers for which effective drugs are urgently needed. Echinatin, a natural compound extracted from Glycyrrhiza plants, has shown promising antitumour effects. However, the efficacy and the direct target of echinatin in cSCC remain unclear.
Purpose:
This study conducted a systematic investigation of the antitumour effects of echinatin on cSCC and the underlying mechanisms involved.
Study Design And Methods:
Three cSCC cell lines, a xenograft model, and a UV-induced cSCC mouse model were used to investigate the potential protective effects of echinatin. The interactions between echinatin and glutathione S-transferase mu3 (GSTM3) and between echinatin and peroxiredoxin-2 (PRDX2) were evaluated by a proteome microarray assay, pull-down LC‒MS/MS analysis, surface plasmon resonance, and molecular docking. The potential mechanisms of GSTM3-mediated echinatin activity were analysed by using western blotting, lentivirus infection and small interfering RNA (siRNA) transfection.
Results:
In this study, we found that echinatin inhibited the proliferation and migration of cSCC cells but had no cytotoxic effect on primary human keratinocytes. Furthermore, echinatin significantly inhibited tumour growth in vivo. Mechanistically, our data showed that echinatin could directly bind to GSTM3 and PRDX2. Notably, echinatin inhibited GSTM3 and PRDX2 levels by promoting their proteasomal degradation, which led to the disruption of ROS production. We then revealed that echinatin increased mitochondrial ROS production by inhibiting GSTM3. Moreover, echinatin triggered ferroptosis by inhibiting GSTM3-mediated ferroptosis negative regulation (FNR) proteins. In addition, echinatin regulated GSTM3-mediated ROS/MAPK signalling.
Conclusion:
Echinatin has good antitumour effects both in vitro and in vivo. Moreover, our findings indicate that GSTM3 and PRDX2 could function as viable targets of echinatin in cSCC. Consequently, echinatin represents a novel treatment for cSCC through the targeting of GSTM3-mediated ferroptosis.
Insights
Echinatin effectively inhibits cutaneous squamous cell carcinoma (cSCC) growth by targeting GSTM3 and PRDX2, promoting cancer cell death through ferroptosis. This natural compound shows promise as a novel therapeutic for cSCC.
Area of Science:
- Oncology
- Dermatology
- Natural Products Chemistry
Background:
- Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer demanding novel therapeutic agents.
- Echinatin, a natural compound from Glycyrrhiza plants, exhibits potential anti-cancer properties, but its role in cSCC is not well-defined.
Purpose of the Study:
- To systematically investigate the anti-tumor effects of echinatin on cSCC.
- To elucidate the underlying molecular mechanisms and direct molecular targets of echinatin in cSCC.
Main Methods:
- Utilized cSCC cell lines, xenograft, and UV-induced mouse models to assess echinatin's efficacy.
- Employed proteome microarray, LC-MS/MS, SPR, and molecular docking to identify echinatin's direct targets (GSTM3 and PRDX2).
- Investigated mechanisms via western blotting, lentivirus, and siRNA to analyze GSTM3-mediated pathways.
Main Results:
- Echinatin inhibited cSCC cell proliferation and migration without affecting normal keratinocytes.
- Echinatin demonstrated significant in vivo tumor growth inhibition.
- Echinatin directly binds to GSTM3 and PRDX2, promoting their proteasomal degradation, disrupting ROS production, increasing mitochondrial ROS, and triggering ferroptosis via GSTM3 inhibition.
Conclusions:
- Echinatin exhibits significant anti-tumor activity against cSCC in vitro and in vivo.
- GSTM3 and PRDX2 are identified as direct molecular targets of echinatin in cSCC.
- Echinatin represents a novel therapeutic strategy for cSCC by targeting GSTM3-mediated ferroptosis.
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