title: The natural tumorcide Manumycin-A targets protein phosphatase 1α and reduces hydrogen peroxide to induce lymphoma apoptosis.
abstract: Numerous compounds for treating human disease have been discovered in nature. Manumycin-A (Man-A) is a natural, well-tolerated microbial metabolite and a potent experimental tumoricide. We recently showed that Man-A stimulated reactive oxygen species (ROS) which were upstream of serine/threonine (Ser/Thr) dephosphorylation and caspase-dependent cleavage of MEK and Akt in lymphoma apoptosis. Conversely, activation-specific, Ser/Thr phosphorylation of MEK and Akt proteins was stable in Man-A-resistant tumors suggesting that stimulation of Ser/Thr PPase activity might be required for Man-A tumoricidal activity. Pre-treatment with Calyculin-A, an equipotent inhibitor of PP1 and PP2A, blocked all downstream effects of Man-A whereas, the PP2A-selective inhibitor, Okadaic acid did not, suggesting that PP1 and not PP2A played a role in Man-A action. Phosphorylation of PP1α on Thr320 inhibits its activity. Hence, we posited that if PP1α was important for Man-A action, then Man-A treatment should promote dephosphorylation of PP1α on Thr320. Indeed, T320 was only dephosphorylated in the tumors that underwent apoptosis. Lastly, stable over-expression of a constitutively active PP1α mimetic (PP1αT320A mutant), elevated basal ROS levels and enhanced Man-A-stimulated apoptosis. Taken together, we conclude that PP1α is an important proximal effector of Man-A mediated lymphoma apoptosis and that the mechanisms of Man-A action warrant further investigation.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201, United States; Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, United States; Center for Vascular and Inflammatory Diseases, University of Maryland, Baltimore, MD 21201, United States. Electronic address: Gcarey@som.umaryland.edu.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Carey
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201, United States; Center for Vascular and Inflammatory Diseases, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: Sanjit K
authors.initials: SK
authors.lastname: Roy
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: Hanako
authors.initials: H
authors.lastname: Daino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D019169:Jurkat Cells; D020014:K562 Cells; D008223:Lymphoma; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008387:Marine Toxins; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D008387:Marine Toxins; D010080:Oxazoles; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D014638:Vanadates; C059041:calyculin A; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; D054645:Protein Phosphatase 1; C054474:manumycin
keywords: Akt; Apoptosis; Hydrogen peroxide; Lymphoma; MEK; Manumycin-A; Natural tumoricide; Protein phosphatase 1α, PP1α; Reactive oxygen species; Superoxide