title: The dual PI3K/mTOR inhibitor NVP-BEZ235 prevents epithelial-mesenchymal transition induced by hypoxia and TGF-β1.
abstract: Epithelial-mesenchymal transition (EMT) is regarded as the most important mechanism behind the initiation of cancer metastasis. Though there has been great interest in developing therapies aimed at impairing the process of EMT, only few molecules have been identified to orchestrate it so far. Here we report that the dual PI3K/mTOR inhibitor NVP-BEZ235 is capable of preventing human ovarian cancer cell line SKOV-3 and prostatic cancer cell line PC-3 from hypoxia- and TGF-β1-induced EMT. The addition of NVP-BEZ235 reverses the EMT-like morphologic changes, down-regulation of E-cadherin, and enhancement of cell migration induced by 1% O2 partially through interfering with the expression and transcriptional activity of Hif-1α via PI3K/mTOR pathway. In addition, NVP-BEZ235 inhibits TGF-β1-induced phosphorylation of Smad2/3 and Akt/GSK-3β, reduces the expression of Snail both in transcriptional and post-translational level, and consequently prevents the repression of E-cadherin expression as well as the increase of cell motility caused by TGF-β1. Moreover, in nude mice bearing SKOV-3 ovarian cancer xenografts, NVP-BEZ235 significantly increases the mRNA level of E-cadherin. Taken together, our study demonstrates, for the first time, NVP-BEZ235 can prevent microenvironment and growth factor induced EMT, which suggests this agent as a potential candidate for cancer metastasis treatment.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Guanyu
authors.initials: G
authors.lastname: Lin
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Renhua
authors.initials: R
authors.lastname: Gai
authors.affiliation: College of Materials Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China.
authors.forename: Zibo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Sida
authors.initials: S
authors.lastname: Liao
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Dong
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Auckland Cancer Society Research Centre, the University of Auckland, Auckland, New Zealand.
authors.forename: Yongchuan
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: yang924@zju.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology*; D011897:Random Allocation; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000633:toxicity*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D053773:Transforming Growth Factor beta1; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: EMT; Hypoxia; NVP-BEZ235; PI3K/mTOR; TGF-β1