Abstract
Abstract To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression profiles in individual human prostate cancer specimens before and after chemotherapy collected from previously untreated patients with high-risk, localized disease. Among the molecular signatures associated with treatment, transcripts encoding Inhibitor of DNA Binding 1 (ID1) were significantly upregulated. Among patients who developed biochemical relapse 5 years after chemo-surgery, patients with the ID1 upregulation following chemotherapy had significantly longer relapse-free survival time than patients without ID1 increases. In the prostate cancer LNCaP cell line that is characterized by low ID1 expression, docetaxel dose-dependently induced ID1 expression. This docetaxel-induced ID1 transcription was mediated by ID1 promoter E-box chromatin modification and c-Myc binding. Compared to the empty-vector control, stable ID1 overexpression in LNCaP increased cell proliferation, promoted cell cycle progression through the G1 phase, and enhanced docetaxel-induced cytotoxicity. These phenotypic changes were accompanied by an increase in BCL2 phosphorylation at serine 70, caspase-3 activation and PARP cleavage. In contrast, ID1 siRNA in the LNCaP and C42B cell line reduced cell proliferation and decreased docetaxel-induced cytotoxicity. The ID1-mediated chemosensitivity enhancement was in part due to the ID1-suppression of p21. Overexpression of p21 in LNCaP-ID1 overexpressing cells restored the p21 level and reversed ID1-enhanced chemosensitivity. These data demonstrate that ID1 has a novel therapeutic role in prostate cancer treatment and ID1 upregulation after chemotherapy exposure may be a useful marker of chemotherapy efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5775.
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