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Miltirone induces GSDME-dependent pyroptosis in colorectal cancer by activating caspase 3
Guangwei Zheng1,2, Zhipeng Fang1,2, Zhenlv Lin1,2
1Department of Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
Abstract:
Colorectal cancer (CRC) is a common and malignant tumor, ranking as the third most common cancer in men and the second most common cancer in women. Pyroptosis, a recently described programmed cell death mechanism mediated by the GSDM family, has emerged as an immunogenic mechanism for chemotherapy drugs in tumor treatment. In this study, we discovered that Miltirone has the ability to reduce the viability of CRC cells (SW620 and HCT116) and cause the proteolytic cleavage of gasdermin E (GSDME) in CRC cells. It was also observed that inhibiting GSDME prevented pyroptotic cell death induced by Miltirone in SW620 and HCT116 cells. Furthermore, the main active component of Miltirone was found to effectively bind with caspase 3. SiRNA-mediated caspase 3 silencing and specific caspase 3 inhibitor Z-DEVD-FMK were shown to weaken Miltirone-induced GSDME-dependent cell death. The findings of the study suggest that Miltirone has the potential to inhibit the growth of CRC tumors in vivo by inducing pyroptotic cell death. This indicates that Miltirone could be a viable therapeutic agent for the treatment of CRC through GSDME-dependent pyroptosis. These results offer a promising new option for the clinical treatment of CRC.
Insights
Miltirone reduces colorectal cancer (CRC) cell viability by triggering gasdermin E (GSDME)-dependent pyroptosis, a programmed cell death pathway. This suggests Miltirone is a potential therapeutic agent for CRC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide.
- Pyroptosis, a pro-inflammatory programmed cell death, is mediated by the GSDM family and shows potential in cancer therapy.
- Understanding novel therapeutic mechanisms for CRC is crucial.
Purpose of the Study:
- To investigate the effect of Miltirone on colorectal cancer (CRC) cells.
- To elucidate the role of pyroptosis, specifically gasdermin E (GSDME), in Miltirone's anti-cancer activity.
- To explore the underlying molecular mechanisms involving caspase 3.
Main Methods:
- Cell viability assays on CRC cell lines (SW620, HCT116) treated with Miltirone.
- Assessment of GSDME cleavage and pyroptosis induction.
- GSDME inhibition studies and caspase 3 activity assays (siRNA, specific inhibitor Z-DEVD-FMK).
Main Results:
- Miltirone significantly reduced CRC cell viability.
- Miltirone induced GSDME cleavage and pyroptosis in CRC cells.
- Inhibition of GSDME or caspase 3 attenuated Miltirone-induced pyroptosis, confirming GSDME-dependent cell death.
Conclusions:
- Miltirone effectively induces GSDME-dependent pyroptosis in colorectal cancer cells.
- Miltirone demonstrates potential as a therapeutic agent for CRC by leveraging pyroptosis.
- This study provides a promising avenue for novel CRC treatments targeting GSDME-mediated pyroptosis.
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