title: Ramelteon, a selective MT1/MT2 receptor agonist, suppresses the proliferation and invasiveness of endometrial cancer cells.
abstract: The incidence of endometrial cancer is increasing, making it the fifth most common cancer worldwide. To date, however, there is no standard therapy for patients with recurrent endometrial cancer. Melatonin, a hormone secreted by the pineal gland, has been shown to have anti-tumor effects in various tumor types. Although melatonin is available as a supplement, it has not been approved for cancer treatment. Ramelteon, a selective melatonin receptor type 1 and 2 (MT1/MT2) receptor agonist, has been approved to treat sleep disorders, suggesting that ramelteon may be effective in the treatment of endometrial cancer. To determine whether this agent may be effective in the treatment of endometrial cancer, this study investigated the ability of ramelteon to suppress the proliferation and invasiveness of HHUA cells, an estrogen receptor-positive endometrial cancer cell line. Ramelteon at 10-8M maximally suppressed the proliferation of HHUA cells, reducing the percentage of Ki-67 positive proliferating cells. This effect was completely blocked by luzindole, a MT1/MT2 receptor antagonist. Furthermore, ramelteon inhibited HHUA cell invasion and reduced the expression of the MMP-2 and MMP-9 genes. These results suggested that ramelteon may be a candidate for the treatment of recurrent endometrial cancer, with activity similar to that of melatonin.
authors.affiliation: Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
authors.forename: Kiyono
authors.initials: K
authors.lastname: Osanai
authors.affiliation: Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan. yoichi@ks.kyorin-u.ac.jp.
authors.forename: Yoichi
authors.identifier: http://orcid.org/0000-0002-8474-0625
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Otsu
authors.affiliation: Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Izawa
authors.affiliation: Department of Obstetrics and Gynecology, South Miyagi Medical Center, Miyagi, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Iwashita
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003864:Depression, Chemical; D016889:Endometrial Neoplasms / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D044122:Receptor, Melatonin, MT1 / Q000819:agonists*; D044123:Receptor, Melatonin, MT2 / Q000819:agonists*
chemical_list: D007192:Indenes; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; C495910:ramelteon; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Endometrial cancer; HHUA; Melatonin; Melatonin receptor agonist; Ramelteon