ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21

Hao Geng, Brooks L. Rademacher, Janet Pittsenbarger, Chung Ying Huang, Christopher T. Harvey, Marie C. Lafortune, Anne Myrthue, Mark Garzotto, Peter S. Nelson, Tomasz (Tom) Beer, Zheng (David) Qian

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26 Scopus citations

Abstract

To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression profiles in high-risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy. Among the molecular signatures associated with chemotherapy, transcripts encoding inhibitor of DNA binding 1 (ID1) were significantly upregulated. The patient biochemical relapse status was monitored in a long-term follow-up. Patients with ID1 upregulation were found to be associated with longer relapse-free survival than patients without ID1 increase. This in vivo clinical association was mechanistically investigated. The chemotherapy-induced ID1 upregulation was recapitulated in the prostate cancer cell line LNCaP. Docetaxel dose-dependently induced ID1 transcription, which was mediated by ID1 promoter E-box chromatin modification and c-Myc binding. Stable ID1 overexpression in LNCaP increased cell proliferation, promoted G 1 cell cycle progression, and enhanced docetaxel-induced cytotoxicity. These changes were accompanied by a decrease in cellular mitochondria content, an increase in BCL2 phosphorylation at serine 70, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. In contrast, ID1 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel-induced cytotoxicity by inhibiting cell death. ID1-mediated chemosensitivity enhancement was in part due to ID1 suppression of p21. Overexpression of p21 in LNCaP-ID1-overexpressing cells restored the p21 level and reversed ID1-enhanced chemosensitivity. These molecular data provide a mechanistic rationale for the observed in vivo clinical association between ID1 upregulation and relapse-free survival. Taken together, it shows that ID1 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis.

Original languageEnglish (US)
Pages (from-to)3239-3248
Number of pages10
JournalCancer Research
Volume70
Issue number8
DOIs
Publication statusPublished - Apr 15 2010

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Geng, H., Rademacher, B. L., Pittsenbarger, J., Huang, C. Y., Harvey, C. T., Lafortune, M. C., ... Qian, Z. D. (2010). ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21. Cancer Research, 70(8), 3239-3248. https://doi.org/10.1158/0008-5472.CAN-09-3186