Calyculin A, an inhibitor of protein phosphatases, a potent tumor promoter on CD-1 mouse skin.

Abstract

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.

• Authors: M Suganuma, H Fujiki, H Furuya-Suguri, S Yoshizawa, S Yasumoto, Y Kato, N Fusetani, T Sugimura
• Journal: Cancer research (Cancer Res) Vol. 50 Issue 12 Pg. 3521-5 (Jun 15 1990) ISSN: 0008-5472 [Print] United States
• PMID: 2160320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ethers, Cyclic
• Marine Toxins
• Nuclear Proteins
• Oxazoles
• Phosphoproteins
• RNA-Binding Proteins
• nucleolin
• Okadaic Acid
• 9,10-Dimethyl-1,2-benzanthracene
• calyculin A
• Phosphoprotein Phosphatases

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Animals
• Binding Sites
• Ethers, Cyclic (metabolism, pharmacology)
• Female
• Marine Toxins
• Mice
• Mice, Inbred Strains
• Molecular Weight
• Nuclear Proteins (metabolism)
• Okadaic Acid
• Oxazoles (metabolism, pharmacology)
• Phosphoprotein Phosphatases (antagonists & inhibitors)
• Phosphoproteins (metabolism)
• Phosphorylation
• RNA-Binding Proteins
• Skin (drug effects, metabolism)
• Skin Neoplasms (chemically induced)