Abstract 3005: Inflammasome-independent pyroptosis mediates DHA-led ovarian cancer cell death

Abstract Docosahexaenoic acid (DHA) is a natural compound, which exhibits anti-cancer capability in various cancer types in experimental models. Similar to previous reports in other cancer cell types, we demonstrated that DHA inhibited ovarian cancer cell growth by inducing cell death. In our model, distinct from the effect of DHA on other cancer cell types, we revealed that DHA-induced cell death was only slightly blocked by apoptosis inhibitor (caspase 3 inhibitor DEVD). We characterized the mechanism associated with DHA-led cell death and found that DHA-induced cell death was effectively blocked by caspase 1 inhibitor, indicating that DHA kills ovarian cancer cells by inducing pyroptosis. This mechanism was further supported by the observation that Disulfiram, a Gasdermin D inhibitor, prevented DHA-induced cell death and DHA treatment leads to the cleavage of Gasdermin D. Surprisingly, known inflammasome inhibitors did not affect DHA-induced cell death and Gasdermin D cleavage, ruling out the involvement of the inflammasome for caspase 1 activation. Instead, DHA remarkably elevated the amount of both caspase I and cleaved caspase 1 in ovarian cancer cells. This suggests that DHA activates caspase 1 by augmenting the abundance of caspase 1. Furthermore, we showed that DHA increased the level of intracellular reactive oxygen species (ROS). Use of ROS inhibitor (NAC) abrogated DHA-induced pyroptosis. This study uncovers pyroptosis as the mechanism for DHA-induced ovarian cancer cell death and reveals a previously unknown mechanism for caspase 1 activation. Citation Format: Ozlem Calbay, Shuang Huang. Inflammasome-independent pyroptosis mediates DHA-led ovarian cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3005.