Rubratoxin A specifically and potently inhibits protein phosphatase 2A and suppresses cancer metastasis

Numazu Bio-Medical Research Institute, Microbial Chemistry Research Foundation, Shizuoka.
Cancer Science (Impact Factor: 3.52). 11/2009; 101(3):743-50. DOI: 10.1111/j.1349-7006.2009.01438.x
Source: PubMed


(Cancer Sci 2010; 101: 743–750)
Although cytostatin analog protein phosphatase 2A (PP2A)-specific inhibitors are promising candidates of a new type of anticancer drug, their development has been hindered because of their liability. To find new classes of PP2A-specific inhibitors, we conducted a screening with microbial metabolites and found that rubratoxin A, a classical mycotoxin, is a highly specific and potent inhibitor of the enzyme. While rubratoxin A inhibits PP2A at Ki = 28.7 nm, it hardly inhibited any other phosphatases examined. Rubratoxin B, a close analog, also specifically but weakly inhibits PP2A at Ki = 3.1 μm. The inhibition of intracellular PP2A in cultured cells is obviously observed with 20 μm rubratoxin A treatment for 3 h, inducing the overphosphorylation in PP2A substrate proteins. Although rubratoxins and cytostatin differ in the apparent structures, these compounds share similarities in the structures in detail and PP2A-binding manners. Rubratoxin A showed higher suppression of tumor metastasis and reduction of the primary tumor volume than cytostatin in mouse experiments. As a successor of cytostatin analogs, rubratoxin A should be a good compound leading to the development of antitumor drugs targeting PP2A.

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Available from: Shun-ichi Ohba, Nov 21, 2014
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