Activation of the Raf-1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells.
BACKGROUND
The serine/threonine kinase Raf-1 is a major regulator of the mitogen activated protein kinase (MAPK) pathway, which has been associated with the progression of prostate cancer to the more advanced and androgen-independent disease. Cdc25A phosphatase has been implicated in the regulation of Raf-1 and the MAPK pathway.


METHODS
We used a novel and potent Cdc25A inhibitor, 2,3-bis-[2-hydroxyethylsulfonyl]-[1,4] naphthoquinone (NSC 95397), and its congener (2-mercaptoethanol)-3-methyl-1, 4-naphthoquinone (NSC 672121) to study the role of Cdc25A on the MAPK pathway in human prostate cancer cells.


RESULTS
We found Raf-1 physically interacted with Cdc25A in PC-3 and LNCap cells and inhibitors of Cdc25A induced both extracellular signal-regulated kinase (Erk) activation and Raf-1 tyrosine phosphorylation. NSC 95397 attenuated Cdc25A and Raf-1 interactions due to accelerated degradation of Cdc25A, which was mediated by proteasome degradation. The MAPK kinase (MEK) inhibitor U0126 completely inhibited Erk activation by NSC 95397 and NSC 672121.


CONCLUSIONS
These results indicate Cdc25A phosphatase regulates Raf-1/MEK/Erk kinase activation in human prostate cancer cells.
Nemoto
Kaoru
K
Department of Urology, Nippon Medical School, Tokyo, Japan.
Vogt
Andreas
A
Oguri
Tetsuya
T
Lazo
John S
JS
D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C451261:2,3-bis(2-hydroxyethylsulfanyl)-(1,4)naphthoquinone; D002070:Butadienes; D004791:Enzyme Inhibitors; D007976:Leupeptins; D009285:Naphthoquinones; D009570:Nitriles; C113580:U 0126; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde