Role of Nonreceptor Protein Kinase Ack1 in Prostate Cancer
Abstract
Recent studies from our laboratory have shown that constitutively active Ack1 directly binds and tyrosine phosphorylates the androgen receptor (AR), resulting in ligand-independent AR activity. Moreover, Ack1 transforms LNCaP cells into androgen-independent and highly invasive tumors in nude mice. However, the role of Ack-1 in prostate cancer initiation and progression within the context of a complex organ remains poorly understood. To address this question, we generated transgenic mice expressing a myc-tagged constitutively activate Ack1 transgene in the prostate epithelium, driven by a modified rat probasin promoter. Furthermore, Pb-Ack1 mice were crossed to genetically engineered mice (PTEN+/-and TgAP-T121) that develop high-grade prostate intraepithelial neoplasias (PIN) or adenocarcinoma. Pb-Ack1 prostates presented focal hyperplasia and nuclear atypia as early as 16 weeks of age. These prostatic lesions progressed to mPIN and microinvasive carcinoma as detected in prostates from 49 weeks old Pb-Ack1 mice. Crossing of Pb-Ack1 mice to TgAPT121 mice resulted in accelerated onset of progressive CaP which was detected as early as 24 weeks of age. Furthermore, the apoptotic index was reduced by 50% in bi-transgenic prostates when compared to single TgAPT121 prostates. An increase in serine-phospho-p65 was also observed in the bi-transgenic when compared to the TgAPT121 prostates. Pb-Ack1;Pten+/- compound mice presented mPIN lesions as early as 16 weeks of age. Phospho-serine Akt was detected exclusively in these mPIN lesions, suggesting PTEN loss of heterozygosity. In summary, these data present evidence that Ack-1's oncogenic activity can promote the initiation and progression of prostate cancer in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2010
- Accession Number
- ADA527056
Entities
People
- Charlene Rivera
Organizations
- University of North Carolina at Chapel Hill