E2F1 renders prostate cancer cell resistant to ICAM-1 mediated antitumor immunity by NF-κB modulation

Mol Cancer. 2014 Apr 17;13:84. doi: 10.1186/1476-4598-13-84.

Abstract

Background: E2F1 is the gatekeeper of the cell cycle controlling an analogous balance between proliferation and cell death. E2F1 expression is elevated in advanced prostate cancer. However, it is still unclear that the roles and mechanisms of E2F1 on prostate cancers.

Methods: Targeted knockdown by interferon RNA was applied on two prostate cancer and Hela cell lines to examine the inverse correlation expression of E2F1 and ICAM-1. ICAM-1 promoter reporter and ChIP assays were used for analysis of the molecular basis of transcriptional regulation of E2F1 on ICAM-1. Co-IP assays were employed for testing the protein interaction between E2F1 and NF-κB. Tumor xenograft mice model with E2F1 and ICAM-1-knockdown prostate cancer cells were used to investigate the effects of E2F1 and ICAM-1 on antitumor immunity.

Results: E2F1 knockdown by a specific short hairpin RNA increased gene transcription and protein expression of ICAM-1. By using wild type and a series of mutant ICAM-1 promoter luciferase constructs, the NF-κB binding sites were found to be important for E2F1 regulation of ICAM-1 promoter. Targeted knockdown of E2F1 did not affect expression and phosphorylation of NF-κB and IκBα, but facilitated NF-κB binding to the ICAM-1 promoter, subsequently induced ICAM-1 transcription and production in prostate carcinoma cells. Furthermore, knockdown of E2F1 inhibited tumor growth of prostate cancer in vivo through increasing the susceptibility of tumor cells to ICAM-1-mediated anti-tumor immunity including enhancement of monocyte adhesion, leucocytes infiltration, as well as cytotoxicity against tumor cells.

Conclusions: E2F1 knockdown inhibited prostate tumor growth in vitro and in vivo through sensitizing tumor cells to ICAM-1 mediated anti-immunity by NF-κB modulation, highlighting the potential of E2F1 as a therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • E2F1 Transcription Factor / genetics*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • I-kappa B Proteins / genetics
  • Immunity, Innate / genetics*
  • Intercellular Adhesion Molecule-1 / genetics*
  • Intercellular Adhesion Molecule-1 / isolation & purification
  • Male
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • E2F1 Transcription Factor
  • E2F1 protein, human
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Intercellular Adhesion Molecule-1
  • NF-KappaB Inhibitor alpha