title: Melatonin enhances sensitivity to fluorouracil in oesophageal squamous cell carcinoma through inhibition of Erk and Akt pathway.
abstract: Oesophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-associated death in the world and novel therapeutic alternatives are urgently warranted. In this study, we investigated the anti-tumour activity and underlying mechanisms of melatonin, an indoleamine compound secreted by the pineal gland as well as naturally occurring plant products, in ESCC cells and revealed that melatonin inhibited proliferation, migration, invasion and induced mitochondria-dependent apoptosis of ESCC cells in vitro and suppressed tumour growth in the subcutaneous mice model in vivo. Furthermore, after treatment with melatonin, the expressions of pMEK, pErk, pGSK3β and pAkt were significantly suppressed. In contrast, treatment of the conventional chemotherapeutic drug fluorouracil (5-Fu) resulted in activation of Erk and Akt, which could be reversed by co-treatment with melatonin. Importantly, melatonin effectively enhanced cytotoxicity of 5-Fu to ESCC in vitro and in vivo. Together, these results suggested that inhibition of Erk and Akt pathway by melatonin have an important role in sensitization of ESCC cells to 5-Fu. Combined 5-Fu and melatonin treatment may be appreciated as a useful approach for ESCC therapy that warrants further investigation.
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Yun-Xin
authors: YX
authors: Lu
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Dong-Liang
authors: DL
authors: Chen
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: De-Shen
authors: DS
authors: Wang
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Le-Zong
authors: LZ
authors: Chen
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors: Hai-Yu
authors: HY
authors: Mo
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors: Hui
authors: H
authors: Sheng
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Long
authors: L
authors: Bai
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors: Qi-Nian
authors: QN
authors: Wu
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Hong-En
authors: HE
authors: Yu
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors: Dan
authors: D
authors: Xie
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Jing-Ping
authors: JP
authors: Yun
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors: Zhao-Lei
authors: ZL
authors: Zeng
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Feng
authors: F
authors: Wang
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors: Huai-Qiang
authors: HQ
authors: Ju
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors: Rui-Hua
authors: RH
authors: Xu
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D008550:Melatonin; D005472:Fluorouracil