Abstract
Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine", is known to have anticancer activity, but its underlying mechanism is not completely understood. In this study, we show that celastrol kills several breast and colon cancer cell lines by induction of paraptosis, a cell death mode characterized by extensive vacuolization that arises via dilation of the endoplasmic reticulum (ER) and mitochondria. Celastrol treatment markedly increased mitochondrial Ca2+ levels and induced ER stress via proteasome inhibition in these cells. Both MCU (mitochondrial Ca2+ uniporter) knockdown and pretreatment with ruthenium red, an inhibitor of MCU, inhibited celastrol-induced mitochondrial Ca2+ uptake, dilation of mitochondria/ER, accumulation of poly-ubiquitinated proteins, and cell death in MDA-MB 435S cells. Inhibition of the IP3 receptor (IP3R) with 2-aminoethoxydiphenyl borate (2-APB) also effectively blocked celastrol-induced mitochondrial Ca2+ accumulation and subsequent paraptotic events. Collectively, our results show that the IP3R-mediated release of Ca2+ from the ER and its subsequent MCU-mediatedinflux into mitochondria critically contribute to celastrol-induced paraptosis in cancer cells.
Highlights
Celastrol, a quinone methide triterpene, is a pharmacologically active compound derived from the Chinese medicinal plant, Tripterygium wilfordii [1]
Neither apoptosis nor autophagy is critically involved in celastrol-induced cancer cell death
These results indicate that apoptosis may not critically contribute to the cytotoxicity of celastrol toward the tested cancer cell lines
Summary
A quinone methide triterpene, is a pharmacologically active compound derived from the Chinese medicinal plant, Tripterygium wilfordii [1]. The term “paraptosis” was originally introduced to describe a form of programmed cell death that is morphologically www.impactjournals.com/oncotarget and biochemically distinct from apoptosis [18,19]. It is characterized by: extensive cytoplasmic vacuolization that arises via swelling of the ER [19,20,21] and/or mitochondria [19,21,22]; the lack of characteristic apoptotic features, such as pyknosis, DNA fragmentation and caspase activation [19,21,23]; insensitivity to caspase inhibitors [18,24]; and overexpression of anti-apoptotic Bcl-2-like proteins [18,21,24]. We propose here that the IP3R-mediated release of Ca2+ from the ER and its subsequent mitochondrial Ca2+ uniporter-mediated influx into mitochondria may critically contribute to extensive dilation of mitochondria and the ER, leading to celastrol-induced paraptotic cell death
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