Cdc25 inhibition and cell cycle arrest by a synthetic thioalkyl vitamin K analogue.
2000
A synthetic vitamin K analogue,
2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone or compound 5 (Cpd
5), was found previously to be a potent inhibitor of tumor cell growth.
We now demonstrate that Cpd 5 arrested cell cycle progression at both
G 1 and G 2 -M. Because of the potential arylating
activity of Cpd 5, it might inhibit Cdc25 phosphatases, which contain a
cysteine in the catalytic site. To test this hypothesis, we examined
the inhibitory activity of Cpd 5 against several cell cycle-relevant
protein tyrosine phosphatases and found that Cpd 5 was a potent,
selective, and partially competitive inhibitor of Cdc25 phosphatases.
Furthermore, Cpd 5 caused time-dependent, irreversible enzyme
inhibition, consistent with arylation of the catalytic cysteine in
Cdc25. Treatment of cells with Cpd 5 blocked dephosphorylation of the
Cdc25C substrate, Cdc2, and its kinase activity. Cpd 5 enhanced
tyrosine phosphorylation of both potent regulators of G 1
transition, i.e., Cdk2 and Cdk4, and decreased the
phosphorylation of Rb, an endogenous substrate for Cdk4 kinase.
Furthermore, close chemical analogues that lacked in
vitro Cdc25 inhibitory activity failed to block cell cycle
progression and Cdc2 kinase activity. Cpd 5 did not alter the levels of
p53 or the endogenous cyclin-dependent kinase inhibitors, p21 and p16.
Our results support the hypothesis that the disruption in cell cycle
transition caused by Cpd 5 was attributable to intracellular Cdc25
inhibition. This novel thioalkyl K vitamin analogue could be useful for
cell cycle control studies and may provide a valuable pharmacophore for
the design of future therapeutics.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
40
References
89
Citations
NaN
KQI