title: 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.affiliation: Department of Animal Science, Bharathidasan University, Tiruchirappalli, 620 024, Tamil Nadu, India.
authors.forename: Kandasamy
authors.initials: K
authors.lastname: Palanivel
authors.forename: Veerasamy
authors.initials: V
authors.lastname: Kanimozhi
authors.forename: Balamuthu
authors.initials: B
authors.lastname: Kadalmani
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014255:Trichothecenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D017382:Reactive Oxygen Species; D014255:Trichothecenes; D048051:p38 Mitogen-Activated Protein Kinases; C005348:muconomycin A