Rubratoxin A specifically and potently inhibits protein phosphatase 2A and suppresses cancer metastasis.
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.
Wada
Shun-ichi
S
Numazu Bio-Medical Research Institute, Microbial Chemistry Research Foundation, Shizuoka.
Usami
Ihomi
I
Umezawa
Yoji
Y
Inoue
Hiroyuki
H
Ohba
Shun-ichi
S
Someno
Tetsuya
T
Kawada
Manabu
M
Ikeda
Daishiro
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009183:Mycotoxins / Q000378:metabolism / Q000494:pharmacology*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009183:Mycotoxins; C100297:rubratoxins; D054648:Protein Phosphatase 2