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

Hong Tai Chang, Chiang Ting Chou, I. Shu Chen, Chia Cheng Yu, Ti Lu, Shu Shong Hsu, Pochuen Shieh, Chung Ren Jan, Wei Zhe Liang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

19 Scopus citations

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 [Ca2+]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 Ca2+ signal response induced by cytochalasin B was reduced by removing extracellular Ca2+ and was inhibited by the store-operated Ca2+ channel blocker 2-APB and SKF96365. In Ca2+-free medium, cytochalasin B induced Ca2+ release through thapsigargin-sensitive endoplasmic reticulum stores. Moreover, cytochalasin B increased H2O2 levels but reduced GSH levels. The apoptotic effects evoked by cytochalasin B were partially inhibited by prechelating cytosolic Ca2+ with BAPTA-AM and the antioxidant NAC. Together, in ZR-75-1 cells but not in MCF 10A cells, cytochalasin B activated Ca2+-associated mitochondrial apoptotic pathways that involved G2/M phase arrest and ROS signaling. Furthermore, cytochalasin B induced [Ca2+]i rises by releasing Ca2+ from the endoplasmic reticulum and causing Ca2+ influx through 2-APB or SKF96365-sensitive store-operated Ca2+ entry. Our findings provide new insights into the possible application of cytochalasin B in human breast cancer therapy.

Original languageEnglish
Pages (from-to)1-19
Number of pages19
JournalToxicology
Volume370
DOIs
StatePublished - 31 08 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Ireland Ltd

Keywords

  • Apoptosis
  • Ca
  • Cell cycle
  • Cytochalasin B
  • Human breast cells
  • ROS

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