Mechanism of cell cycle arrest by sulfoquinovosyl monoacylglycerol with a C18-saturated fatty acid (C18-SQMG).
We have screened the inhibitors of mammalian DNA polymerases from natural products, and in the process found that either sulfoglycolipids or sulfoquinovosyl monoacylglycerol with a C18-saturated fatty acid (C18-SQMG), potently and selectively inhibited the activity of mammalian DNA polymerase (pol) and moderately the pol alpha. C18-SQMG was a cancer cell growth suppressor and a promissive anti-tumor agent. The purpose of this study was to elucidate the cell growth inhibition mechanism of C18-SQMG using HeLa cells. Analyses of the cell cycle and cyclin expression suggested that C18-SQMG arrested the cell cycle at intra-S phase, and the inhibition manner of DNA replication by C18-SQMG was similar to that by hydroxyurea. However, the DNA replication block by C18-SQMG did not induce degradation of Cdc25A protein, which was required for the replication block by hydroxyurea. C18-SQMG somewhat delayed mitosis because it induced phosphorylation of protein kinases, such as checkpoint kinases 1 and 2. These results suggest that C18-SQMG at first blocked DNA replication at the S phase by inhibiting replicative DNA polymerases, such as alpha, and then as the result of the inhibition, the other checkpoint signals associated with the pol might have responded.
Murakami
Chikako
C
Laboratory of Food and Nutritional Science, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
Miuzno
Takeshi
T
Hanaoka
Fumio
F
Yoshida
Hiromi
H
Sakaguchi
Kengo
K
Mizushina
Yoshiyuki
Y
D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D005989:Glycerides / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000378:metabolism
D002843:Chromatin; D016213:Cyclins; D005227:Fatty Acids; D005989:Glycerides; D004259:DNA-Directed DNA Polymerase; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D006918:Hydroxyurea