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.
Highlights
Prostate cancer is the most common cancer in men and the second leading cause of cancer deaths in the United States [1, 2]
Our results show that combined treatment of SR48692 and radiation effectively kills cancer cells in vitro and in vivo and suggest the need for clinical testing to establish whether anti-neurotensin receptor 1 (NTR1) treatment combined with radiotherapy may increase local control of the tumor and decrease its metastatic potential
Cell lines and reagents PC-3M-luc-C6 (PC-3M) human prostate carcinoma cell line transfected with the luciferase gene was purchased from Xenogen Corporation, which provided luciferin
Summary
Prostate cancer is the most common cancer in men and the second leading cause of cancer deaths in the United States [1, 2]. Radiotherapy is one of the standard treatment modalities for prostate cancer [3]; a major obstacle to effective radiotherapy is the limited radiation dose that can be safely delivered to the prostate An alternative to radiation dose increase would be to use radiosensitizing agents selectively targeted to prostate cancer cells while sparing normal tissue, minimizing radiation toxicity by lowering effective therapeutic doses. Several different factors could participate in prostate cancer development, progression, and resistance to antitumor therapy. One of such possible mechanisms involves intraprostate
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