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Cholestane-3β,5α,6β-triol Induces Multiple Cell Death in A549 Cells via ER Stress and Autophagy Activation
Jiaxi Chen1, Jieping Zhang1, Lijuan Cai1
1School of Medicine, Tongji University, 1239 Si-Ping Road, Shanghai 200092, China.
Abstract:
Cholestane-3β,5α,6β-triol (CT) and its analogues are abundant in natural sources and are reported to demonstrate cytotoxicity toward different kinds of tumor cells without a deep probe into their mechanism of action. CT is also one of the major metabolic oxysterols of cholesterol in mammals and is found to accumulate in various diseases. An extensive exploration of the biological roles of CT over the past few decades has established its identity as an apoptosis inducer. In this study, the effects of CT on A549 cell death were investigated through cell viability assays. RNA-sequencing analysis and western blot of CT-treated A549 cells revealed the role of CT in inducing endoplasmic reticulum (ER) stress response and enhancing autophagy flux, suggesting a putative mechanism of CT-induced cell-death activation involving reactive oxygen species (ROS)-mediated ER stress and autophagy. It is reported for the first time that the upregulation of autophagy induced by CT can serve as a cellular cytotoxicity response in accelerating CT-induced cell death in A549 cells. This research provides evidence for the effect of CT as an oxysterol in cell response to oxidative damage and allows for a deep understanding of cholesterol in its response in an oxidative stress environment that commonly occurs in the progression of various diseases.
Insights
Cholestane-3β,5α,6β-triol (CT) induces cancer cell death by promoting endoplasmic reticulum stress and autophagy. This study reveals CT
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Cholestane-3β,5α,6β-triol (CT) is a cholesterol metabolite found in mammals and implicated in various diseases.
- CT and its analogues exhibit cytotoxicity against tumor cells, but their mechanisms remain unclear.
- Previous research identified CT as an apoptosis inducer.
Purpose of the Study:
- To investigate the effects of CT on A549 lung cancer cell death.
- To elucidate the underlying molecular mechanisms of CT-induced cytotoxicity.
- To explore the role of ER stress and autophagy in CT-mediated cell death.
Main Methods:
- Cell viability assays were performed on A549 cells treated with CT.
- RNA-sequencing analysis was conducted to assess gene expression changes.
- Western blot was used to examine protein levels related to ER stress and autophagy.
Main Results:
- CT treatment led to significant A549 cell death.
- RNA-seq and western blot revealed CT induces endoplasmic reticulum (ER) stress.
- CT was found to enhance autophagy flux, suggesting a role in cell death.
- Autophagy upregulation acts as a cytotoxic response accelerating CT-induced cell death.
Conclusions:
- CT induces A549 cell death through a mechanism involving ROS-mediated ER stress and autophagy.
- The study demonstrates that CT-induced autophagy accelerates cell death.
- This research deepens the understanding of cholesterol oxysterol roles in oxidative stress and disease.
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