Abstract P4-07-10: Epithelial-mesenchymal transition sensitizes breast cancer cells to paraptosis-mediated cell death via the fungus-derived sesterpenoid, Ophiobolin A

Abstract

Abstract The epithelial-mesenchymal transition (EMT) enables the dissociation of cancer cells from the primary tumor by facilitating tolerance to lack of cell-adhesion, decreasing cellular division and increasing motility of individual cells, which leads to an invasive phenotype that links EMT to metastasis. Furthermore, EMT results in the acquisition of stem-cell markers and an increased ability to initiate tumor growth, supporting the concept that EMT may contribute to the development of a small, persistent sub-population of the tumor called cancer stem cells (CSCs). Cells that have undergone EMT have characteristically suppressed cell cycles, making them resistant to commonly used chemotherapies that target DNA replication or microtubule dynamics, processes essential to replicating cells. Nonspecific treatments can also rely on inducing apoptotic cell death; however, recent debates challenge the efficacy of apoptosis in solid tumors, citing high rates of acquired resistance. Utilizing a compound that induces alternative cell death, namely paraptosis, becomes attractive when these other treatments fail. Relying on an activated gene expression program, paraptosis results in the swelling of the mitochondria and endoplasmic reticulum and Apaf-1-independent alternative caspase-9 activity. Treating with paraptosis-inducing compounds such as Ophiobolin A (OpA) specifically targets otherwise-insensitive CSC and EMT cells to re-sensitize bulk tumor populations to chemotherapies. We describe EMT as a key driver of enhanced sensitivity to paraptosis-induced cell death following short-term treatment with OpA or other paraptosis-inducing compounds. Further, paraptosis selectively eliminates the CSC sub-population by reducing stem cell activity and highlights the potential of this pathway in breast cancer treatment. Citation Format: Reisenauer K, Tao Y, Ingros A, Philip T, Evidente A, Kornienko A, Romo D, Taube J. Epithelial-mesenchymal transition sensitizes breast cancer cells to paraptosis-mediated cell death via the fungus-derived sesterpenoid, Ophiobolin A [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-10.