Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7.

Abstract

Verrucarin A (VA), an active constituent of pathogenic fungus Myrothecium verrucaria, which has the ability to inhibit the growth of breast cancer cells. However, the mechanism by which VA exerts its inhibitory potential remains elusive. Here, we demonstrated that VA inhibited the growth of MCF-7 breast cancer cells, increased the levels of reactive oxygen species (ROS), and subsequently induced mitochondrial membrane potential (Δψm) loss, leading to the increase of Bax/Bcl-2 ratio, cytochrome c release, caspase activation, PARP degradation, and apoptosis. VA effectively increased the phosphorylation of p38MAPK and diminished the phosphorylation of ERK/Akt. In addition, VA caused cell cycle deregulation through the induction of p21 and p53. Furthermore, ROS scavenger (n-acetyl-L-cysteine) and p38MAPK inhibitor (SB202190) effectively abrogated the VA-induced cell cycle deregulation and apoptosis. Conversely, U0126, an ERK1/2 inhibitor, enhanced the VA-induced apoptotic signals. Taken together, our results suggest that VA-induces apoptosis and cell cycle deregulation in MCF-7 cells through ROS-dependent p38MAPK activation.

• Authors: Kandasamy Palanivel, Veerasamy Kanimozhi, Balamuthu Kadalmani
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 35 Issue 10 Pg. 10159-67 (Oct 2014) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 25027398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Cell Cycle Proteins
• Reactive Oxygen Species
• Trichothecenes
• p38 Mitogen-Activated Protein Kinases
• muconomycin A

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (metabolism)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Enzyme Activation (drug effects)
• Flow Cytometry
• Humans
• In Situ Nick-End Labeling
• MCF-7 Cells
• Membrane Potential, Mitochondrial (drug effects)
• Reactive Oxygen Species (metabolism)
• Trichothecenes (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)