期刊
MOLECULAR CANCER THERAPEUTICS
卷 10, 期 1, 页码 29-36出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-10-0778
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资金
- Susan G. Komen [KG080540]
- Department of Defense Prostate Cancer Research [PC073951]
- Marlene Harris-Ride Cincinnati Pilot
- PHS [P30 DK078392]
- China Medical University and Hospital
- MDACC
- [RO1 CA109311]
- [DOH99-TD-C-111-005]
- [NSC-2632-B-001-MY3]
- [R01 CA125379]
- NATIONAL CANCER INSTITUTE [R01CA125379, R01CA109311, P01CA099031] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK078392] Funding Source: NIH RePORTER
The proliferation cell nuclear antigen (PCNA) is a critical protein required for DNA replication in proliferating cells including cancer cells. However, direct inhibition of PCNA in cancer cells has been difficult due to the lack of targetable sites. We previously reported that phosphorylation of tyrosine 211 (Y211) on PCNA is important for the proliferative function of PCNA when this protein is associated with the chromatin in cancer cells. Here, we show that the Y211 phosphorylation of PCNA is a frequent event in advanced prostate cancer. To explore the potential of this signaling event in inhibition of cancer cell growth, we used a synthetic peptide, the Y211F peptide, which when present inhibits phosphorylation of Y211 on endogenous PCNA. Treatment with this peptide, but not a scrambled control peptide, resulted in S-phase arrest, inhibition of DNA synthesis, and enhanced cell death in a panel of human prostate cancer cell lines. In addition, treatment with the Y211F peptide led to decreased tumor growth in PC3-derived xenograft tumors in vivo in nude mice. Our study shows for the first time that PCNA phosphorylation at Y211 is a frequent and biologically important signaling event in prostate cancer. This study also shows a proof of concept that Y211 phosphorylation of PCNA may be used as a therapeutic target in prostate cancer cells, including cells of advanced cancers that are refractory to standard hormonal therapies. Mol Cancer Ther; 10(1); 29-36. (C)2011 AACR.
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