title: PI3K/mTOR dual inhibitor NVP-BEZ235 decreases Mcl-1 expression and sensitizes ovarian carcinoma cells to Bcl-xL-targeting strategies, provided that Bim expression is induced.
abstract: We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Here we assessed the anticancer potential of combining ABT-737-induced inhibition of Bcl-xL with Mcl-1 inhibition via PI3K/Akt/mTOR pathway disruption using NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation without inducing apoptosis. It strongly repressed Mcl-1 expression and induced Puma expression in both cell lines tested while differentially modulating Bim between the two. Interestingly, NVP-BEZ235 efficiently sensitized ovarian carcinoma cells to ABT-737, provided that Bim expression was induced. Moreover, inhibiting the ERK1/2 pathway restored Bim expression and sensitized low Bim-expressing cancer cells to the BEZ235/ABT-737 treatment.
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Abdelghani
authors.initials: A
authors.lastname: Jebahi
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France; (d)On secondment from ISPB, Faculte de Pharmacie, Universite Lyon 1, Lyon, France. Electronic address: m.villedieu@baclesse.unicancer.fr.
authors.forename: Marie
authors.initials: M
authors.lastname: Villedieu
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Pétigny-Lechartier
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Brotin
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Louis
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Edwige
authors.initials: E
authors.lastname: Abeilard
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Giffard
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France.
authors.forename: Marika
authors.initials: M
authors.lastname: Guercio
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Briand
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Gauduchon
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France; Clinical Research Department, François Baclesse Comprehensive Cancer Centre, Caen, France; Oncologic Uro-Gynaecology Department, François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lheureux
authors.affiliation: Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Poulain
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; D007093:Imidazoles; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D013449:Sulfonamides; D051020:bcl-X Protein; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C531198:dactolisib
keywords: ABT-737; Bim; ERK1/2; Mcl-1; NVP-BEZ235; Ovarian cancer