Molecular mechanism of adaphostin-mediated G1 arrest in prostate cancer (PC-3) cells: signaling events mediated by hepatocyte growth factor receptor, c-Met, and p38 MAPK pathways.

Abstract

Adaphostin (NSC680410), a small molecule congener of tyrphostin AG957, has been demonstrated previously to have significant anti-proliferative effects in several leukemia models. However, this effect of adaphostin in adherent cells/solid tumor models has not been examined. In this study, we investigated the anti-proliferative effects of adaphostin in the human prostate cancer cell line PC-3. Specifically, we explored the potential molecular mechanism(s) by which adaphostin elicits its anti-proliferative effect(s). We demonstrate that adaphostin inhibits the proliferation of PC-3 cells by inducing a G(1) phase cell cycle arrest. This adaphostin-induced G(1) arrest was associated with an increase in the expression of p21 and p27 and a decrease in the expression of G(1)-specific cyclins (cyclin A, D1, and D3) and cyclin-dependent kinases 4 and 6. Consequently, a dramatic decrease in the phosphorylation of retinoblastoma protein was also observed. Additionally, we found that adaphostin treatment induced a decrease in the phosphorylation of nucleophosmin, a major nuclear phosphoprotein, and that this decreased phosphorylation was a result of the p21- and p27-mediated inactivation of cyclin E-cyclin-dependent kinase 2 complex kinase activity. Furthermore, we have determined that the adaphostin-mediated cell cycle arrest of PC-3 cells is dependent upon activation of the p38 MAPK. We also demonstrate that the hepatocyte growth factor receptor-c-Met is involved in the adaphostin-mediated signaling events that regulate p38 MAPK. Taken together, these results identify for the first time a signaling cascade of adaphostin-mediated G(1) phase-specific cell cycle arrest in PC-3 cells. These findings suggest that the tyrphostin member has a broader spectrum of activity than originally predicted.

• Authors: Indranil Mukhopadhyay, Edward A Sausville, James H Doroshow, Krishnendu K Roy
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 49 Pg. 37330-44 (Dec 08 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16956884 (Publication Type: Journal Article)

Chemical References

• CDKN1A protein, human
• Cyclin E
• Cyclin-Dependent Kinase Inhibitor p21
• Hydroquinones
• NSC 680410
• Nuclear Proteins
• Nucleoplasmins
• Phosphoproteins
• RNA, Small Interfering
• Cyclin-Dependent Kinase Inhibitor p27
• Proto-Oncogene Proteins c-met
• CDK2 protein, human
• Cyclin-Dependent Kinase 2
• p38 Mitogen-Activated Protein Kinases
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Base Sequence
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin E (metabolism)
• Cyclin-Dependent Kinase 2 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• G1 Phase (drug effects)
• Humans
• Hydroquinones (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Male
• Models, Biological
• Nuclear Proteins (metabolism)
• Nucleoplasmins
• Phosphoproteins (metabolism)
• Phosphorylation
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)