Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
Carcinogenesis. 2019 May 14;40(3):422-431. doi: 10.1093/carcin/bgy186.
5-Fluorouracil (5-FU) has been established as the first-line chemotherapy for advanced colorectal cancer (CRC); however, acquired chemoresistance is often the cause of poor therapeutic response. Melatonin is a molecule that is associated with circadian rhythms. Although antitumor effects of melatonin have been shown, the underlying mechanism(s) for its activity and its effect, if any, in chemoresistant CRC has not been studied. We aimed to investigate antitumor effects of melatonin, and more specifically its effect on molecular mechanisms in 5-FU resistant CRC cells.
The cell growth was assessed in CRC cells, patient-derived organoids and 5-FU resistant CRC cells after treatments with melatonin. In addition, the expression of thymidylate synthase (TYMS) and microRNAs (miRNAs) that are targeting TYMS were examined.
We observed that melatonin inhibited the cell growth in 5-FU resistant CRC cells. In addition, we found that melatonin significantly promoted apoptosis. Furthermore, a combination of melatonin and 5-FU markedly enhanced 5-FU-mediated cytotoxicity in 5-FU resistant cells. In addition, melatonin significantly decreased the expression of TYMS. Interestingly, this effect was manifested through the simultaneous increase in the expression of miR-215-5p, for which, TYMS serves as the direct downstream target for this miRNA.
Melatonin facilitates overcoming 5-FU resistance through downregulation of TYMS. Melatonin may serve as a potential therapeutic option on its own, or in conjunction with 5-FU, in the treatment of patients with advanced or chemoresistant CRC.Melatonin inhibits the growth of 5-FU resistant colorectal cancer (CRC) cells through upregulation of miR-215-5p and a concomitant downregulation of TYMS. Melatonin may serve as a potential therapeutic option in the treatment of patients with advanced or chemoresistant CRC.
5-氟尿嘧啶（5-FU）已被确立为晚期结直肠癌（CRC）的一线化疗药物；然而，获得性耐药性常常是治疗反应不佳的原因。褪黑素是一种与昼夜节律相关的分子。尽管已经证明了褪黑素具有抗肿瘤作用，但它的作用机制及其在耐药性 CRC 中的作用（如果有的话）尚未得到研究。我们旨在研究褪黑素的抗肿瘤作用，更具体地说，研究其对 5-FU 耐药 CRC 细胞中分子机制的影响。
用褪黑素处理 CRC 细胞、患者来源的类器官和 5-FU 耐药 CRC 细胞后，评估细胞生长情况。此外，还检测了胸苷酸合成酶（TYMS）的表达和靶向 TYMS 的 microRNAs（miRNAs）。
我们观察到褪黑素抑制了 5-FU 耐药 CRC 细胞的生长。此外，我们发现褪黑素显著促进了细胞凋亡。此外，褪黑素和 5-FU 的联合使用显著增强了 5-FU 耐药细胞中的 5-FU 介导的细胞毒性。此外，褪黑素显著降低了 TYMS 的表达。有趣的是，这种作用是通过 miR-215-5p 的表达同时增加来实现的，TYMS 是该 miRNA 的直接下游靶标。
褪黑素通过下调 TYMS 促进克服 5-FU 耐药。褪黑素本身或与 5-FU 联合使用，可能成为治疗晚期或耐药性 CRC 患者的潜在治疗选择。褪黑素通过上调 miR-215-5p 和同时下调 TYMS 抑制 5-FU 耐药结直肠癌（CRC）细胞的生长。褪黑素可能成为治疗晚期或耐药性 CRC 患者的潜在治疗选择。
