Chrysophanol selectively represses breast cancer cell growth by inducing reactive oxygen species production and endoplasmic reticulum stress via AKT and mitogen-activated protein kinase signal pathways

Sunwoo Park, Whasun Lim, Gwonhwa Song

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8 Citations (Scopus)

Abstract

Breast cancer is a leading lethal gynecological cancer. Although many tumor markers and target genes have been studied in breast cancer, its incidence is increasing. Recently, the therapeutic effects of natural phytochemicals have been studied in various cancers as adjuvants. Chrysophanol is an anti-inflammatory, anti-angiogenetic, and anti-tumor anthraquinone but has not been widely studied in cancers. Here, we verified the anti-cancer effects and cellular mechanism of chrysophanol in human breast cancer cells (BT-474 and MCF-7). Chrysophanol selectively inhibited cell proliferation and induced apoptosis of breast cancer cells but not of normal mammary ductal epithelial cells, MCF-12A. Additionally, chrysophanol increased loss of mitochondrial membrane potential and cytosolic calcium levels to activate pro-apoptotic proteins, Bax, Bak, and cytochrome c, in both cell lines. Reactive oxygen species (ROS) overproduction by chrysophanol resulted in endoplasmic reticulum (ER) stress, leading to an increase in PERK, eIF2α, GADD153, and IRE1α levels in BT-474 and MCF-7 cells. These ER stress proteins increased by chrysophanol were repressed by co-treatment with N-acetyl-L-cysteine, an ROS inhibitor. Western blotting showed that chrysophanol down-regulated ERK1/2, AKT, P70S6K, and S6 in both cell lines. However, P38 and JNK activities decreased in BT-474 cells and increased in MCF-7 cells. Additionally, co-treatment with ERK1/2 (U0126) or an AKT inhibitor (LY294002) plus chrysophanol reduced cell proliferation, whereas P38 (SB203580) and a JNK inhibitor (SP600125) showed synergic effects only in BT-474 cell lines. These results show that chrysophanol has anti-cancer effects on human breast cancer cells, specifically through mitochondrial apoptosis and ER stress induction.

Original languageEnglish
Pages (from-to)201-211
Number of pages11
JournalToxicology and Applied Pharmacology
Volume360
DOIs
Publication statusPublished - 2018 Dec 1

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Keywords

  • BT-474
  • Chrysophanol
  • ER stress
  • MCF-7
  • Mitochondria-dependent apoptosis

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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