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Inhibition Of Neuropetide-Mediated Prostate Cancer Progression By Specific Src Kinase Inhibitor Azd0530
UroToday.com - Joy C Yang, PhD and collaborators from Univerisity of California, Davis state that neuropeptides such as gastrin-releasing peptide (GRP)/bombesin may modify AR through Src kinase and steer AR gene transactivation activities. They investigated the GRP/bombesin-mediated AR activation in androgen-sensitive LNCaP cells and hypothesized that inhibition of Src activity in vitro and in vivo may block neuropeptide-mediated AR activation and tumor progression.
GRP overexpressing LNCaP cells (LNCaP-GRP) were developed through transfection and selection. Xenograft tumors grown in nude mice with the LNCaP-GRP cells were re-cultured and termed GRP-Pro cells. Binding of AR to the promoter regions of the PSA gene in LNCaP cells was assessed by chromatin immunoprecipitation (ChIP). Src and Fak activation was determined by Western blotting. Inhibition of proliferation and migration of LNCaP-GRP and GRP-Pro cells were performed with the MTT assay and the Boyden chamber, respectively. Severe Combined Immunodeficient (SCID) mice were implanted with GRP-Pro cells to study the inhibition of tumor progression by AZD0530.
Exogenous bombesin phosphorylates AR and this is completely inhibited by the specific Src inhibitor AZD0530. AR binding to the PSA promoter is preferential to the proximal promoter region in LNCaP-GRP cells, whereas predominant binding in parental LNCaP cells stimulated by androgen was to the enhancer region. ChiP assay demonstrated that ACTR, an AR co-activator is also involved in this differential binding. AZD0530 inhibits GRP-Pro cell proliferation and migration through complete inhibition of Src kinase activation at Y416. This in turns inhibits phosphorylation of Fak that complexes with Src upon GRP/bombesin stimulation by more than 70%. AZD0530 inhibited neuropeptide primary tumor growth in only 2/7 mice, but prevented all metastasis in 100% of treated mice. All control mice demonstrated metastasis. The conclude that targeting Src kinase is an important strategy for inhibition of neuropeptide mediated androgen-independent CaP.
From the 2007 annual meeting of the AUA.
Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS
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Inhibarea Neuropetide mediate de cãtre progresia cancerului de prostatã specifice src inhibitor kinaza Azd0530 - Inhibition Of Neuropetide-Mediated Prostate Cancer Progression By Specific Src Kinase Inhibitor Azd0530 - articole medicale engleza - startsanatate
