Mechanisms underlying effect of the mycotoxin cytochalasin B on induction of cytotoxicity, modulation of cell cycle, Ca2+ homeostasis and ROS production in human breast cells. (31st August 2016)

• Record Type: Journal Article
• Authors: Chang, Hong-Tai; Chou, Chiang-Ting; Chen, I.-Shu; Yu, Chia-Cheng; Lu, Ti; Hsu, Shu-Shong; Shieh, Pochuen; Jan, Chung-Ren; Liang, Wei-Zhe
• Is Part Of: Toxicology. Volume 370(2016)
• Page Start: 1
• Page End: 19
• Publication Date: 2016-08-31
• Subjects: Apoptosis -- Ca2+ -- Cell cycle -- Cytochalasin B -- Human breast cells -- ROS; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2016.09.006
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: Molecular effects of the mycotoxin cytochalasin B were explored in human breast cells. In ZR-75-1 cells, cytochalasin B induced G2/M phase arrest that involved p53, p27, p21, cyclin B1 and CDK1 regulation. In ZR-75-1 cells, cytochalasin B activated Ca 2+ -associated mitochondrial apoptotic pathways that involved ROS production. Abstract: Cytochalasin B, a cell-permeable mycotoxin isolated from the fungus Phoma spp., shows a wide range of biological effects, among which its potent antitumor activity has raised great interests in different models. However, the cytotoxic activity of cytochalasin B and its underlying mechanisms have not been elucidated in breast cells. This study examined the effect of cytochalasin B on MCF 10A human breast epithelial cells and ZR-75-1 human breast cancer cells. Cytochalasin B (10–20 μM) concentration-dependently induced cytotoxicity, cell cycle arrest, and [Ca 2+ ]i rises in ZR-75-1 cells but not in MCF 10A cells. In ZR-75-1 cells, cytochalasin B triggered G2/M phase arrest through the modulation of CDK1, cyclin B1, p53, p27 and p21 expressions. The Ca 2+ signal response induced by cytochalasin B was reduced by removing extracellular Ca 2+ and was inhibited by the store-operated Ca 2+ channel blocker 2-APB and SKF96365. In Ca 2+ -free medium, cytochalasin B induced Ca 2+ release through thapsigargin-sensitive endoplasmic reticulum stores. Moreover, cytochalasin B increased H2 O2 levels but reduced GSH levels. The apoptotic effects evoked by cytochalasin B were partially inhibited by prechelating cytosolic Ca 2+ with BAPTA-AM and the antioxidant NAC. Together, in ZR-75-1 cells but not in MCF 10A cells, cytochalasin B activated Ca 2+ -associated mitochondrial apoptotic pathways that involved G2/M phase arrest and ROS signaling. Furthermore, cytochalasin B induced [Ca 2+ ]i rises by releasing Ca 2+ from the endoplasmic reticulum and causing Ca 2+ influx through 2-APB or SKF96365-sensitive store-operated Ca 2+ entry. Our findings provide new insights into the possible application of cytochalasin B in human breast cancer therapy.