Abstract 4326: CDK7/CDK9 mediates transcriptional regulation to prime cancer cell paraptosis

Abstract

Abstract The mechanisms underlying progression in cell paraptosis are largely unknown. CPYPP, cyclosporin A, and curcumin incited cytoplasmic vacuolization and induced paraptosis in breast cancer cells. The paraptotic program evolved with reactive oxygen species (ROS) provocation and overactivation of proteostatic dynamics to elicit transcriptional regulation involved in redox homeostasis and proteostasis. Pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drives paraptotic progression in a reciprocally-dependent manner with heat shock proteins (HSPs). Proteostatic stress as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolding protein response, as well as ROS provocation primarily within the nucleus enforced CDK7/CDK9-Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R (PKR) in a forward loop to amplify the transcriptional regulation and thereby exacerbate proteotoxicity leading to overt paraptosis. Xenograft mouse with OECM-1 cells further confirmed the paraptotic induction against tumor growth. A novel regulatory paradigm that activation of CDK7/CDK9-Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis therefore was concluded. Citation Format: Ling-Chu Chang, Shih-Kai Chiang, Shuen-Ei Chen. CDK7/CDK9 mediates transcriptional regulation to prime cancer cell paraptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4326.