Rubratoxin A specifically and potently inhibits protein phosphatase 2A and suppresses cancer metastasis.
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| Abstract |
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 microM. The inhibition of intracellular PP2A in cultured cells is obviously observed with 20 microM 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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| Authors | Shun-ichi Wada, Ihomi Usami, Yoji Umezawa, Hiroyuki Inoue, Shun-ichi Ohba, Tetsuya Someno, Manabu Kawada, Daishiro Ikeda |
| Journal | Cancer science (Cancer Sci) Vol. 101 Issue 3 Pg. 743-50 (Mar 2010) ISSN: 1349-7006 [Electronic] England |
| PMID | 20028386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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