title: Neurotensin receptor1 antagonist SR48692 reduces proliferation by inducing apoptosis and cell cycle arrest in melanoma cells.
abstract: 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.
authors.affiliation: Department of Dermatology, the Third Hospital of Hebei Medical University, 139 Ziqiang Rd, Shijiazhuang, 050000, Hebei, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shunqin
authors.initials: S
authors.lastname: Zhu
authors.forename: Liang
authors.initials: L
authors.lastname: Yi
authors.forename: Yaling
authors.initials: Y
authors.lastname: Liu
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Cui
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009496:Neurotensin / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D011720:Pyrazoles; D011804:Quinolines; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; C079087:SR 48692; D009496:Neurotensin