Release of Ca2+ from the endoplasmic reticulum and its subsequent influx into mitochondria trigger celastrol-induced paraptosis in cancer cells

Mi Jin Yoon, A. Reum Lee, Soo Ah Jeong, You Sun Kim, Jin Yeop Kim, Yong Jun Kwon, Kyeong Sook Choi*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

111 Citations (Scopus)

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-mediated influx into mitochondria critically contribute to celastrol-induced paraptosis in cancer cells.

Original languageEnglish
Pages (from-to)6816-6831
Number of pages16
JournalOncotarget
Volume5
Issue number16
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Ca
  • Celastrol
  • Endoplasmic reticulum
  • Mitochondria
  • Paraptosis

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