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Gasdermin D Cleavage and Cytokine Release, Indicative of Pyroptotic Cell Death, Induced by Ophiobolin A in Breast
Santhalakshmi Ranganathan1, Tolulope Ojo1, Alagu Subramanian1
1Department of Biology, Baylor University, Waco, TX 76706, USA.
Abstract:
An unmet challenge in managing breast cancer is treatment failure due to resistance to apoptosis-inducing chemotherapies. Thus, it is important to identify novel non-apoptotic therapeutic agents. Several non-apoptotic programmed cell death pathways utilize specific cellular signaling events to trigger lytic and pro-inflammatory cell death, examples of which are pyroptosis and necroptosis. Our study illustrates that ophiobolin A (OpA) is an anti-cancer agent that triggers lytic cell death in breast cancer cells, including triple-negative breast cancer (TNBC). This study reveals that OpA induces typical pyroptosis-like characteristics, including cellular swelling, plasma membrane rupture, GSDMD cleavage, and release of cytokines in breast cancer cells. However, the additional involvement of RIPK1 and induction of RIPK3 clustering in select cell lines suggest that multiple pathways may be triggered upon OpA treatment. The induction of pro-inflammatory cell death suggests potential applications for OpA in cancer treatment.
Insights
Ophiobolin A triggers inflammatory cell death in breast cancer, offering a novel therapeutic strategy beyond traditional chemotherapy resistance. This non-apoptotic cell death pathway shows promise for treating triple-negative breast cancer (TNBC).
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Breast cancer treatment faces challenges due to resistance to apoptosis-inducing chemotherapies.
- Novel non-apoptotic therapeutic agents are crucial for overcoming treatment failure.
- Lytic and pro-inflammatory programmed cell death pathways, such as pyroptosis and necroptosis, offer alternative cell death mechanisms.
Purpose of the Study:
- To investigate ophiobolin A (OpA) as a novel anti-cancer agent.
- To determine if OpA can induce non-apoptotic cell death in breast cancer cells, including triple-negative breast cancer (TNBC).
- To elucidate the specific cell death pathways triggered by OpA.
Main Methods:
- Treatment of breast cancer cells with ophiobolin A (OpA).
- Assessment of cell death characteristics, including cellular swelling, plasma membrane rupture, and cytokine release.
- Analysis of key protein markers and signaling pathways involved in pyroptosis and necroptosis, such as GSDMD, RIPK1, and RIPK3.
Main Results:
- OpA induces lytic cell death in breast cancer cells, including TNBC.
- OpA treatment exhibits pyroptosis-like features: cellular swelling, plasma membrane rupture, GSDMD cleavage, and cytokine release.
- Evidence suggests potential involvement of RIPK1 and RIPK3 clustering, indicating activation of multiple cell death pathways.
Conclusions:
- Ophiobolin A is a potent inducer of lytic, pro-inflammatory cell death in breast cancer.
- OpA's mechanism, potentially involving pyroptosis and necroptosis pathways, presents a promising alternative to apoptosis-based therapies.
- OpA demonstrates significant potential as a therapeutic agent for breast cancer, particularly TNBC, by circumventing chemoresistance.
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