Activation of the Raf-1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells.

Abstract

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.

• Authors: Kaoru Nemoto, Andreas Vogt, Tetsuya Oguri, John S Lazo
• Journal: The Prostate (Prostate) Vol. 58 Issue 1 Pg. 95-102 (Jan 01 2004) ISSN: 0270-4137 [Print] United States
• PMID: 14673957 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• 2,3-bis(2-hydroxyethylsulfanyl)-(1,4)naphthoquinone
• Butadienes
• Enzyme Inhibitors
• Leupeptins
• Naphthoquinones
• Nitriles
• U 0126
• Proto-Oncogene Proteins c-raf
• Mitogen-Activated Protein Kinases
• CDC25A protein, human
• cdc25 Phosphatases
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Blotting, Western
• Butadienes (pharmacology)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Humans
• Leupeptins (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Male
• Mitogen-Activated Protein Kinases (metabolism)
• Naphthoquinones (pharmacology)
• Nitriles (pharmacology)
• Phosphorylation
• Prostatic Neoplasms (enzymology)
• Proto-Oncogene Proteins c-raf (metabolism)
• cdc25 Phosphatases (antagonists & inhibitors, metabolism)