Malignant melanoma is highly aggressive, and always resistant to conventional chemo-radiotherapy, which results in poor prognosis. As a specific antagonist of neurotensin receptor 1 (NTSR1), emerging evidences confirmed that SR48692 can reverse the pro-growth effect of neurotensin (NTS) by interrupting the interaction between NTS and NTSR1. A375 melanoma cell line was used in this experiment, and SR48692 was employed as the inhibitor of NTS/NTSR1 pathway. We detected the expression of NTSR1 by NTSR1 immunofluorescence and Western blot. After SR48692 treatment, cell proliferation was determined by cell counting, MTT assay and BrdU incorporation study, the cell cycle and apoptosis were performed by flow cytometry. At last Soft Agar Clonogenic assay and xenograft cancer mice model in vivo were used to confirm our result. In this study, we showed that NTSR1 is commonly high expressed in melanoma cells, but low expressed in normal immortalized human keratinocyte line HaCaT. SR48692 not only reduced cell proliferation and self-renewal potential in vitro, but also inhibited the tumor growth derived from A375 cells in NOD/SCID mice in vivo. Further, we originally reported that SR48692 inhibited cell proliferation through cell cycle arrest and apoptosis. Considering the favorable toxicity profile in vitro and in vivo though targeting NTS/NTSR1, SR48692 is worthy of further study and exploitation in melanoma treatment.
This is a preview of subscription content, log in to check access.
This study was supported by the National Basic Research Program of China (No. 2012cb114603), the National Natural Science Foundation of China (No. 31271462, 31172268, 81201551).
Disclosure of interest
The authors declare no conflict of proprietary, commercial, or financial interest in the products or companies described in this article.
Carraway R, Leeman SE (1973) The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 248(19):6854–6861PubMedGoogle Scholar
Dupouy S, Mourra N, Doan VK, Gompel A, Alifano M, Forgez P (2011) The potential use of the neurotensin high affinity receptor 1 as a biomarker for cancer progression and as a component of personalized medicine in selective cancers. Biochimie 93(9):1369–1378PubMedCrossRefGoogle Scholar
Davis TP, Burgess HS, Crowell S, Moody TW, Culling-Berglund A, Liu RH (1989) β-Endorphin and neurotensin stimulate in vitro clonal growth of human SCLC cells. Eur J Pharmacol 161(2–3):283–285PubMedCrossRefGoogle Scholar
Sehgal I, Powers S, Huntley B, Powis G, Pittelkow M, Maihle NJ (1994) Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer. Proc Natl Acad Sci 91(11):4673–4677PubMedCentralPubMedCrossRefGoogle Scholar
Seethalakshmi L, Mitra S, Dobner P, Menon M, Carraway R (1997) Neurotensin receptor expression in prostate cancer cell line and growth effect of NT at physiological concentrations. Prostate 31(3):183–192PubMedCrossRefGoogle Scholar
Iwase K, Evers B, Hellmich M, Kim H, Higashide S, Gully D et al (1996) Indirect inhibitory effect of a neurotensin receptor antagonist on human colon cancer (LoVo) growth. Surg Oncol 5(5):245–251PubMedCrossRefGoogle Scholar
Maoret JJ, Anini Y, Rouyer-Fessard C, Gully D, Laburthe M (1999) Neurotensin and a non-peptide neurotensin receptor antagonist control human colon cancer cell growth in cell culture and in cells xenografted into nude mice. Int J Cancer 80(3):448–454PubMedCrossRefGoogle Scholar
Iwase K, Evers BM, Hellmich MR, Kim HJ, Higashide S, Gully D et al (1997) Inhibition of neurotensin-induced pancreatic carcinoma growth by a nonpeptide neurotensin receptor antagonist, SR48692. Cancer 79(9):1787–1793PubMedCrossRefGoogle Scholar
Yamada M, Ohata H, Momose K, Richelson E (1995) Pharmacological characterization of SR 48692 sensitive neurotensin receptor in human pancreatic cancer cells, MIA PaCa-2. Res Commun Mol Pathol Pharmacol 90(1):37PubMedGoogle Scholar
Mijatovic T, Gailly P, Mathieu V, De Nève N, Yeaton P, Kiss R et al (2007) Neurotensin is a versatile modulator of in vitro human pancreatic ductal adenocarcinoma cell (PDAC) migration. Anal Cell Pathol 29(4):315–326Google Scholar
Souazé F, Dupouy S, Viardot-Foucault V, Bruyneel E, Attoub S, Gespach C et al (2006) Expression of neurotensin and NT1 receptor in human breast cancer: a potential role in tumor progression. Cancer Res 66(12):6243–6249PubMedCrossRefGoogle Scholar
Dal Farra C, Sarret P, Navarro V, Botto JM, Mazella J, Vincent JP (2001) Involvement of the neurotensin receptor subtype NTR3 in the growth effect of neurotensin on cancer cell lines. Int J Cancer 92(4):503–509PubMedCrossRefGoogle Scholar
Collier N, Bloom S, Hodgson H, Weinbren K, Lee Y, Blumgart L (1984) Neurotensin secretion by fibrolamellar carcinoma of the liver. The Lancet. 323(8376):538–540CrossRefGoogle Scholar
Moody TW, Carney DN, Korman LY, Gazdar AF, Minna JD (1985) Neurotensin is produced by and secreted from classic small cell lung cancer cells. Life Sci 36(18):1727–1732PubMedCrossRefGoogle Scholar
Di Sant’Agnese Anthony (1992) P. Neuroendocrine differentiation in human prostatic carcinoma. Hum Pathol 23(3):287–296PubMedCrossRefGoogle Scholar
Reubi JC, Waser B, Schaer JC, Laissue JA (1999) Neurotensin receptors in human neoplasms: high incidence in Ewing’s sarcomas. Int J Cancer 82(2):213–218PubMedCrossRefGoogle Scholar
Alifano M, Souazé F, Dupouy S, Camilleri-Broët S, Younes M, Ahmed-Zaïd S-M et al (2010) Neurotensin receptor 1 determines the outcome of non-small cell lung cancer. Clin Cancer Res 16(17):4401–4410PubMedCrossRefGoogle Scholar
Gully D, Canton M, Boigegrain R, Jeanjean F, Molimard J-C, Poncelet M et al (1993) Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor. Proc Natl Acad Sci 90(1):65–69PubMedCentralPubMedCrossRefGoogle Scholar
Gully D, Jeanjean F, Poncelet M, Steinberg R, Soubrie P, Fur GL et al (1995) Neuropharmacological profile of non-peptide neurotensin antagonists. Fundam Clin Pharmacol 9(6):513–521PubMedCrossRefGoogle Scholar
Rostene W, Azzi M, Boudin H, Lepee I, Souaze F, MENDEZ-UBACH M et al (1997) Use of nonpeptide antagonists to explore the physiological roles of neurotensin. Ann N Y Acad Sci 814(1):125–141PubMedCrossRefGoogle Scholar
Dobner PR, Deutch AY, Fadel J (2003) Neurotensin: dual roles in psychostimulant and antipsychotic drug responses. Life Sci 73(6):801–811PubMedCrossRefGoogle Scholar
Chen L, Yung K, Yung W (2006) Neurotensin selectively facilitates glutamatergic transmission in globus pallidus. Neuroscience 141(4):1871–1878PubMedCrossRefGoogle Scholar
Petkova-Kirova P, Rakovska A, Della Corte L, Zaekova G, Radomirov R, Mayer A (2008) Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis. Brain Res Bull 77(2):129–135PubMedCrossRefGoogle Scholar
Petkova-Kirova P, Rakovska A, Zaekova G, Ballini C, Corte LD, Radomirov R et al (2008) Stimulation by neurotensin of dopamine and 5-hydroxytryptamine (5-HT) release from rat prefrontal cortex: possible role of NTR1 receptors in neuropsychiatric disorders. Neurochem Int 53(6):355–361PubMedCrossRefGoogle Scholar