Calyculin A, an inhibitor of protein phosphatases, a potent tumor promoter on CD-1 mouse skin.
Calyculin A, isolated from a marine sponge, has a novel spiro ketal skeleton. Structurally unrelated to okadaic acid, calyculin A bound to the okadaic acid receptors in particulate and soluble fractions of mouse skin. The biochemical and tumor-promoting activities of calyculin A were studied with those of okadaic acid. Calyculin A inhibited the activity of protein phosphatases, which serve as the okadaic acid receptors. The effective dose of calyculin A for 50% inhibition was 0.3 nM, similar to that of okadaic acid. Like okadaic acid, calyculin A induced ornithine decarboxylase in mouse skin and hyperphosphorylation of a Mr 60,000 protein in human papilloma virus type 16-transformed human keratinocytes. A two-stage carcinogenesis experiment on mouse skin, initiated by 100 micrograms (390 nmol) of 7,12-dimethylbenz(a)anthracene and followed by 1 microgram (1.0 nmol) of calyculin A, revealed that calyculin A is an additional member of the okadaic acid class of tumor promoters. The percentages of tumor-bearing mice in the groups treated with DMBA plus calyculin A, and with DMBA followed by 1 microgram (1.2 nmol) of okadaic acid were 86.7 and 80.0%, respectively, in week 30. The mechanisms of action of calyculin A and okadaic acid, in addition to dinophysistoxin-1 (35-methylokadaic acid), are discussed. Calyculin A is the first tumor promoter to be screened by the okadaic acid receptor binding test.
Suganuma
M
M
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan.
Fujiki
H
H
Furuya-Suguri
H
H
Yoshizawa
S
S
Yasumoto
S
S
Kato
Y
Y
Fusetani
N
N
Sugimura
T
T
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001665:Binding Sites; D004988:Ethers, Cyclic / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D008387:Marine Toxins; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D009687:Nuclear Proteins / Q000378:metabolism; D019319:Okadaic Acid; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D016601:RNA-Binding Proteins; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced*; D000097796:Nucleolin
D015127:9,10-Dimethyl-1,2-benzanthracene; D004988:Ethers, Cyclic; D008387:Marine Toxins; D009687:Nuclear Proteins; D019319:Okadaic Acid; D010080:Oxazoles; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C059041:calyculin A