Journal
EXPERIMENTAL CELL RESEARCH
Volume 332, Issue 1, Pages 136-145Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2014.12.009
Keywords
Manumycin-A; Natural tumoricide; Lymphoma; Apoptosis; Protein phosphatase 1 alpha, PP1 alpha; Reactive oxygen species; Hydrogen peroxide; Superoxide; MEK; Akt
Categories
Funding
- National Cancer Institute/National Institutes of Health (NCI) [CA-94027, CA-122882, UH2CA-158689]
- University of Maryland School of Medicine [GC00432490]
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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 PP1 alpha on Thr320 inhibits its activity. Hence, we posited that if PP1 alpha was important for Man-A action, then Man-A treatment should promote dephosphorylation of PP1 alpha on Thr320. Indeed, T320 was only dephosphorylated in the tumors that underwent apoptosis. Lastly, stable over-expression of a constitutively active PP1 alpha mimetic (PPl alpha T320A mutant), elevated basal ROS levels and enhanced Man-A-stimulated apoptosis. Taken together, we conclude that PP1 alpha is an important proximal effector of Man-A mediated lymphoma apoptosis and that the mechanisms of Man-A action warrant further investigation. Published by Elsevier Inc.
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