title: Verrucarin A induces apoptosis through ROS-mediated EGFR/MAPK/Akt signaling pathways in MDA-MB-231 breast cancer cells.
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.
authors: Department of Animal Science, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India.
authors: Kandasamy
authors: K
authors: Palanivel
authors: Veerasamy
authors: V
authors: Kanimozhi
authors: Balamuthu
authors: B
authors: Kadalmani
authors: Mohammad Abdulkader
authors: MA
authors: Akbarsha
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014255:Trichothecenes / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D014255:Trichothecenes; C005348:muconomycin A
keywords: APOPTOSIS; EPIDERMAL GROWTH FACTOR RECEPTOR; MAPK; REACTIVE OXYGEN SPECIES; VERRUCARIN A