Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation

Cancer Res. 2011 Nov 1;71(21):6817-26. doi: 10.1158/0008-5472.CAN-11-1646. Epub 2011 Sep 8.

Abstract

Radiotherapy combined with androgen depletion is generally successful for treating locally advanced prostate cancer. However, radioresistance that contributes to recurrence remains a major therapeutic problem in many patients. In this study, we define the high-affinity neurotensin receptor 1 (NTR1) as a tractable new molecular target to radiosensitize prostate cancers. The selective NTR1 antagonist SR48692 sensitized prostate cancer cells in a dose- and time-dependent manner, increasing apoptotic cell death and decreasing clonogenic survival. The observed cancer selectivity for combinations of SR48692 and radiation reflected differential expression of NTR1, which is highly expressed in prostate cancer cells but not in normal prostate epithelial cells. Radiosensitization was not affected by androgen dependence or androgen receptor expression status. NTR1 inhibition in cancer cell-attenuated epidermal growth factor receptor activation and downstream signaling, whether induced by neurotensin or ionizing radiation, establish a molecular mechanism for sensitization. Most notably, SR48692 efficiently radiosensitized PC-3M orthotopic human tumor xenografts in mice, and significantly reduced tumor burden. Taken together, our findings offer preclinical proof of concept for targeting the NTR1 receptor as a strategy to improve efficacy and outcomes of prostate cancer treatments using radiotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / pathology
  • Adenocarcinoma / radiotherapy*
  • Androgens
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / radiation effects
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / physiology
  • Neoplasms, Hormone-Dependent / pathology
  • Neoplasms, Hormone-Dependent / radiotherapy
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / radiotherapy*
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / radiation effects
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Quinolines / pharmacology
  • Quinolines / therapeutic use*
  • Radiation Tolerance / drug effects
  • Radiation Tolerance / physiology
  • Radiation-Sensitizing Agents / pharmacology
  • Radiation-Sensitizing Agents / therapeutic use*
  • Receptors, Androgen / analysis
  • Receptors, Neurotensin / antagonists & inhibitors*
  • Receptors, Neurotensin / physiology
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays

Substances

  • Androgens
  • Neoplasm Proteins
  • Pyrazoles
  • Quinolines
  • Radiation-Sensitizing Agents
  • Receptors, Androgen
  • Receptors, Neurotensin
  • neurotensin type 1 receptor
  • SR 48692
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors