title: Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition.
abstract: Selenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimize its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and reactive oxygen species production were analysed in A549 cells. FOXO3a subcellular localization was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Av Diagonal 643, Barcelona 08028, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain. Electronic address: mtarrado@ub.edu.
authors.forename: Míriam
authors.initials: M
authors.lastname: Tarrado-Castellarnau
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Av Diagonal 643, Barcelona 08028, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain. Electronic address: roldancortes@ub.edu.
authors.forename: Roldán
authors.initials: R
authors.lastname: Cortés
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Av Diagonal 643, Barcelona 08028, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain. Electronic address: mzanuy@hotmail.com.
authors.forename: Miriam
authors.initials: M
authors.lastname: Zanuy
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Av Diagonal 643, Barcelona 08028, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain. Electronic address: joseptarrago11@gmail.com.
authors.forename: Josep
authors.initials: J
authors.lastname: Tarragó-Celada
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Av Diagonal 643, Barcelona 08028, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain. Electronic address: ihapolat@gmail.com.
authors.forename: Ibrahim H
authors.initials: IH
authors.lastname: Polat
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal; Regenerative Medicine Program, Department of Biomedical Sciences and Medicine University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal; Brain Tumour Research Centre, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom. Electronic address: drrjhill@gmail.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Hill
authors.affiliation: Department of Toxicology, Markey Cancer Center and Center for Environmental and Systems Biochemistry (CESB), University of Kentucky, Lexington, KY 40536, USA. Electronic address: twmfan@gmail.com.
authors.forename: Teresa W M
authors.initials: TW
authors.lastname: Fan
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal; Regenerative Medicine Program, Department of Biomedical Sciences and Medicine University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal. Electronic address: walink@ualg.pt.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Link
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Av Diagonal 643, Barcelona 08028, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain. Electronic address: martacascante@ub.edu.
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D051379:Mice; D016566:Organoselenium Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C008493:methylselenic acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: Akt; Cisplatin; Cisplatin (PubChem CID: 441203); FOXO; LY294002 (PubChem CID: 3973); Methylseleninic acid; Methylseleninic acid (PubChem CID: 161597); PI3K; Selenium; Sodium selenite (PubChem CID: 24934)