title: SMAD signaling and redox imbalance cooperate to induce prostate cancer cell dormancy.
abstract: Metastasis involves the dissemination of single or small clumps of cancer cells through blood or lymphatic vessels and their extravasation into distant organs. Despite the strong regulation of metastases development by a cell dormancy phenomenon, the dormant state of cancer cells remains poorly characterized due to the difficulty of in vivo studies. We have recently shown in vitro that clonogenicity of prostate cancer cells is regulated by a dormancy phenomenon that is strongly induced when cells are cultured both at low cell density and in a slightly hypertonic medium. Here, we characterized by RT-qPCR a genetic expression signature of this dormant state which combines the presence of both stemness and differentiation markers. We showed that both TFGβ/BMP signaling and redox imbalance are required for the full induction of this dormancy signature and cell quiescence. Moreover, reconstruction experiments showed that TFGβ/BMP signaling and redox imbalance are sufficient to generate a pattern of genetic expression displaying all characteristic features of the dormancy signature. Finally, we observed that low cell density was sufficient to activate TGFβ/BMP signaling and to generate a slight redox imbalance thus priming cells for dormancy that can be attained with a co-stimulus like hypertonicity, most likely through an increased redox imbalance. The identification of a dual regulation of dormancy provides a framework for the interpretation of previous reports showing a restricted ability of BMP signaling to regulate cancer cell dormancy in vivo and draws attention on the role of oxidative stress in the metastatic process.
authors.affiliation: a LBPA ; UMR8113 ENSC - CNRS; Ecole Normale Supérieure de Cachan ; Cachan , France.
authors.forename: Anh Thu
authors.initials: AT
authors.lastname: Bui
authors.forename: Fanny
authors.initials: F
authors.lastname: Laurent
authors.forename: Maryline
authors.initials: M
authors.lastname: Havard
authors.forename: François
authors.initials: F
authors.lastname: Dautry
authors.forename: Thierry
authors.initials: T
authors.lastname: Tchénio
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D006861:Hydrogen Peroxide; D005978:Glutathione
keywords: ARM, Averaging Ratio Method; BSO, buthionine sulfoximine; CE, cloning efficiency; DMEM-FCS, Dulbecco Modified Essential Medium supplemented with 10% Fetal Calf Serum and penicillin-streptomycin; LD_hyper, low cell density condition in DMEM-FCS medium; LD_hypo, low cell density condition in hypotonic medium made by addition of 25% water to DMEM-FCS; MD_hyper, medium cell density condition in DMEM-FCS medium (slightly hypertonic); MD_hypo, medium cell density condition in hypotonic medium made by addition of 25% water to DMEM-FCS; NAM, Normalized Averaging Method; SMAD transcription factor; cell proliferation; cell signaling; prostate cancer; redox regulation