Inhibition of Neurotensin Receptor 1 Selectively Sensitizes Prostate Cancer to Ionizing Radiation

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. Cancer Res; 71(21);

Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors

“…In cell cultures, NTSR 1 expression increases with the tumorigenic potential of cancer cells (30). NTSR 1 was also reported to be involved in resistance to radiotherapy (29).…”

“…Early studies noted that neurotensin and neurotensin receptors are recruited in advanced prostate cancer as an alternative growth pathway in the absence of androgens (28). NTSR 1 is expressed in prostate cancer cells but not in normal prostate epithelial cells (29). In cell cultures, NTSR 1 expression increases with the tumorigenic potential of cancer cells (30).…”

“…GRPR expression is positively correlated with androgen receptor expression, and GRPR imaging might be most sensitive in the early stage of disease or in patients with biochemical-relapse "prostatespecific antigen rise" who are not on androgen-deprivation therapy. Contrarily, the NTSR 1 pathway appears to be activated by androgen deprivation, suggesting a role for NTSR 1 imaging during the switch to castration-resistant disease (28)(29)(30).…”

Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

“…The neuroendocrine differentiation (NED) of prostate cancer cells is closely correlated with radioresistance (43,185). In the prostate gland, neuroendocrine (NE) cells are < 1% of total epithelial cells; however, the number of NE-like cells increases in advanced prostate cancer (129).…”

Application of liposomes in drug development &ndash; focus on gastroenterological targets

“…107 The selective neurotensin receptor 1 (NTR-1) antagonist sensitized prostate cancer cells to radiation therapy. 108 Functionalization with neurotensin peptides significantly improved the ability of liposomes to deliver chemotherapeutics into CRC cells and resulted in a four fold increase in cytotoxicity. 109 Her2 and VEGFR are overexpressed in many cancer types including gastric cancer 110 and CRC.…”