title: miR-491-5p-induced apoptosis in ovarian carcinoma depends on the direct inhibition of both BCL-XL and EGFR leading to BIM activation.
abstract: We sought to identify miRNAs that can efficiently induce apoptosis in ovarian cancer cells by overcoming BCL-X(L) and MCL1 anti-apoptotic activity, using combined computational and experimental approaches. We found that miR-491-5p efficiently induces apoptosis in IGROV1-R10 cells by directly inhibiting BCL-X(L) expression and by inducing BIM accumulation in its dephosphorylated form. This latter effect is due to direct targeting of epidermal growth factor receptor (EGFR) by miR-491-5p and consequent inhibition of downstream AKT and MAPK signalling pathways. Induction of apoptosis by miR-491-5p in this cell line is mimicked by a combination of EGFR inhibition together with a BH3-mimetic molecule. In contrast, SKOV3 cells treated with miR-491-5p maintain AKT and MAPK activity, do not induce BIM and do not undergo cell death despite BCL-XL and EGFR downregulation. In this cell line, sensitivity to miR-491-5p is restored by inhibition of both AKT and MAPK signalling pathways. Altogether, this work highlights the potential of miRNA functional studies to decipher cell signalling pathways or major regulatory hubs involved in cell survival to finally propose the rationale design of new strategies on the basis of pharmacological combinations.
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: C
authors.initials: C
authors.lastname: Denoyelle
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France [4] CNRS, Délégation régionale Ile-de-France Est, 94532 Thiais cedex, France.
authors.forename: B
authors.initials: B
authors.lastname: Lambert
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: M
authors.initials: M
authors.lastname: Meryet-Figuière
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: N
authors.initials: N
authors.lastname: Vigneron
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: E
authors.initials: E
authors.lastname: Brotin
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: C
authors.initials: C
authors.lastname: Lecerf
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: E
authors.initials: E
authors.lastname: Abeilard
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: F
authors.initials: F
authors.lastname: Giffard
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: M-H
authors.initials: MH
authors.lastname: Louis
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: P
authors.initials: P
authors.lastname: Gauduchon
authors.affiliation: 1] Team 8 Cell survival and tumor escape in breast cancer, UMR 892 INSERM/6299 CNRS, Université de Nantes, Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France [2] Institut de Cancérologie de l'Ouest (ICO), Centre de Lutte contre le Cancer René Gauducheau, Angers, France.
authors.forename: P
authors.initials: P
authors.lastname: Juin
authors.affiliation: 1] Normandie Univ, Caen, France [2] UNICAEN BioTICLA Unit (Biology and innovative therapeutics of locally aggressive cancers) EA4656, Caen, France [3] Comprehensive Cancer Center François Baclesse, UNICANCER, Caen, France.
authors.forename: L
authors.initials: L
authors.lastname: Poulain
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C551410:MIRN491 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D051020:bcl-X Protein; C512478:EGFR protein, human; D066246:ErbB Receptors