title: Plumbagin induces apoptosis in lymphoma cells via oxidative stress mediated glutathionylation and inhibition of mitogen-activated protein kinase phosphatases (MKP1/2).
abstract: Maintaining cellular redox homeostasis is imperative for the survival and normal functioning of cells. This study describes the role and regulation of MAPKinases in oxidative stress mediated apoptosis. Plumbagin, a vitamin K3 analog and a pro-oxidant, was employed and it induced apoptosis in both mouse and human T-cell lymphoma cell lines via increased oxidative stress, caspase activity and loss of mitochondrial membrane potential. The pro-oxidant and cytotoxic effects of plumbagin were sensitive to antioxidants indicating a decisive role of cellular redox balance. Plumbagin induced persistent activation of JNK and pharmacological inhibition as well as shRNA-mediated JNK knock-down rescued cells from plumbagin-induced apoptosis. Further, plumbagin induced cytochrome c release, FasL expression and Bax levels via activation of JNK pathway. Exposure of lymphoma cells to plumbagin led to inhibition of total and specific phosphatase activity, increased total protein S-glutathionylation and induced glutathionylation of dual specific phosphatase- 1 and 4 (MKP-1 and MKP-2). The in vivo anti-tumor efficacy of plumbagin was demonstrated using a mouse model. In conclusion, oxidative stress mediated tumor cytotoxicity operates through sustained JNK activation via a novel redox-mediated regulation of MKP-1 and MKP-2.
authors.affiliation: Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Checker
authors.affiliation: Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Gambhir
authors.affiliation: Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Solid State Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India. Electronic address: sskumar@barc.gov.in.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sandur
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D009285:Naphthoquinones / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D011897:Random Allocation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009285:Naphthoquinones; D054639:Mitogen-Activated Protein Kinase Phosphatases; C517019:DUSP1 protein, human; C490583:DUSP4 protein, human; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D005978:Glutathione; C014758:plumbagin
keywords: Caspase; GSH/GSSG; JNK; ROS; Vitamin K3