title: Mevalonate pathway is a therapeutic target in esophageal squamous cell carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most common lethal tumors in the world. Thus, it is very urgent to develop new therapeutic targets against this disease. The mevalonate (MVA) pathway, paced by its rate-limiting enzyme, hydroxymethylglutaryl coenzyme A reductase, is required for the generation of several fundamental end products including cholesterol and isoprenoids. The function of the MVA pathway in ESCC has not been investigated. In this study, it was found that the MVA pathway was upregulated in ESCC clinical samples. Statin, the inhibitor of the MVA pathway, exerted potent cytotoxicity against human ESCC cells by inhibiting cell growth and proliferation, while it exerted lesser effects on non-tumorigenic SHEE cells. Further study revealed that statin could potently induce cell apoptosis and cell cycle arrest and also dose-dependently inhibit the growth of xenograft tumors in nude mice. With regard to the molecular mechanism, statin treatment was related to decreased extracellular signal-regulated kinase activation and proliferating cell nuclear antigen, cyclin D1 expression, and increased cleavage of poly(ADP-ribose) polymerase. Taken together, our findings suggest that the MVA pathway plays an important role in the progression of ESCC by modulating cell growth and statin might be a potential therapeutic agent in ESCC.
authors.affiliation: Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Rd, Shanghai, 200030, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Ji
authors.initials: J
authors.lastname: Zhu
authors.forename: Heng
authors.initials: H
authors.lastname: Zhao
authors.forename: Chenxi
authors.initials: C
authors.lastname: Zhong
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Yao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D019938:Cyclin D1; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D011065:Poly(ADP-ribose) Polymerases; D048049:Extracellular Signal-Regulated MAP Kinases; D008798:Mevalonic Acid