Verrucarin A Induces Apoptosis Through ROS-Mediated EGFR/MAPK/Akt Signaling Pathways in MDA-MB-231 Breast Cancer Cells

• Published in: Journal of cellular biochemistry 2014-11, Vol.115 (11), p.2022-2032
• Main Authors: Palanivel, Kandasamy, Kanimozhi, Veerasamy, Kadalmani, Balamuthu, Akbarsha, Mohammad Abdulkader
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - pharmacology; APOPTOSIS; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; EPIDERMAL GROWTH FACTOR RECEPTOR; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; MAP Kinase Signaling System - drug effects; MAPK; Membrane Potential, Mitochondrial - drug effects; REACTIVE OXYGEN SPECIES; Reactive Oxygen Species - metabolism; Trichothecenes - pharmacology; VERRUCARIN A
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.24874

ABSTRACT The present study was carried out to elucidate the mechanisms underlying Verrucarin A (VA)‐induced cytotoxicity in human breast cancer cell line MDA‐MB‐231. VA inhibited the growth of MDA‐MB‐231 cells by induction of reactive oxygen species (ROS)‐dependent mitochondrial apoptosis. Elevation of ROS production, associated with changes in Bax/Bcl‐2 ratio, led to loss of mitochondrial membrane potential (Δψm) and cytochrome c release in VA‐treated cells. Release of cytochrome c from mitochondria to cytosol triggered activation of caspase‐3, PARP cleavage, DNA fragmentation, and finally apoptotic cell death. Furthermore, VA‐induced apoptosis was accompanied by the activation of p38MAPK and inhibition of phosphorylation of EGFR as well as of Akt and ERK1/2. However, pre‐treatment with n‐acetyl cysteine, an ROS scavenger, and SB202190, a p38MAPK inhibitor, significantly inhibited VA‐induced ROS generation, EGFR inhibition, p38MAPK activation and apoptosis. Moreover, pharmacological inhibition of EGFR and ERK1/2 significantly accelerated the VA‐induced apoptosis in MDA‐MB‐231 cells. Collectively, these results indicate that VA‐induces ROS elevation in cancer cells, which results in the activation of p38MAPK and inhibition of EGFR/Akt/ERK signaling cascade and, ultimately, cancer cell death. J. Cell. Biochem. 115: 2022–2032, 2014. © 2014 Wiley Periodicals, Inc.