Abstract A8: Cdk5 modulates ErbB2/3 phosphorylation and prostate cancer cell growth

Abstract

Abstract Prostate cancer is an age-related carcinoma and the most commonly diagnosed malignancy in men. We have previously demonstrated a pivotal role for cyclin-dependent kinase (Cdk) 5 activity in modulating the proliferation on thyroid cancer cells. Cdk5 was originally defined as a trophic player in neurons and has been reported to phosphorylate ErbB2/3 and mediate ErbB2/3 activity. ErbB2/3 receptors are mentioned to be important to cancer cell survival. In recent decade, Cdk5 becomes a new target of interests in cancer research. Furthermore, Cdk5 activity is indicated to control cell motility and metastasis of prostate cancer. Initially, our immunohistochemical analysis on prostatic specimen revealed that five out of eight (62.5%) patients expressed relatively higher Cdk5 proteins in clinical tumor tissues than individual normal ones. Next, a Cdk inhibitor roscovitine (Rv, also named Seliciclib or CYC202, a clinical trial drug on non-small cell lung cancer and leukemia) was utilized to inhibit Cdk5 activity in prostate cancer cell line LNCaP. Rv treatment resulted in significant growth inhibition and morphology change of LNCaP cells. The results of in vitro kinase assay also exhibited that the activity of Cdk5 but not Cdk1 was obviously diminished by Rv. Then the association and co-localization between Cdk5 and ErbB2/3 in LNCaP cells were identified and this interaction could be interfered by Rv treatment. In addition, the serine phosphorylation of ErbB2/3 was reduced by inhibition of Cdk5 activity. Moreover, Rv further decreased the phosphorylation of Akt, Erk and STAT3 which were downstream signals of ErbB2/3 in the presence of heregulin (HRG, ligand of ErbB3) treatment. Finally, Rv dramatically blocked the HRG-stimulated growth of LNCaP cells. According to these results, we found that Cdk5 might regulate survival pathways through ErbB2/3 phosphorylation. Therefore, we suggest that Cdk5 may be a potential therapeutic target in prostate or other cancers. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A8.