Gasdermin D Cleavage and Cytokine Release, Indicative of Pyroptotic Cell Death, Induced by Ophiobolin A in Breast Cancer Cell Lines

TL;DR

Ophiobolin A causes pyroptotic cell death in breast cancer cells, offering a new potential treatment approach.

Contribution

Ophiobolin A is shown to induce pyroptosis in breast cancer cells, including triple-negative breast cancer.

Findings

Ophiobolin A induces pyroptosis-like features such as cell swelling and membrane rupture in breast cancer cells.

Ophiobolin A causes cleavage of Gasdermin D and cytokine release in breast cancer cells.

RIPK1 and RIPK3 are involved in Ophiobolin A-induced cell death in some breast cancer cell lines.

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.

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