title: Inhibition of mTORC1 activity by REDD1 induction in myeloma cells resistant to bortezomib cytotoxicity.
abstract: The combination of bortezomib and dexamethasone is becoming the reference induction treatment for multiple myeloma patients younger than 65 years. Despite its advantage over vincristin adryamicin dexamethasone induction treatment, bortezomib does not benefit all patients. We hypothesize that heterogeneity of the response experienced by myeloma patients is, at least in part, due to genomic variations in the malignant plasma cells. To test this hypothesis we used gene expression profiling to identify early responsive genes induced by bortezomib in resistant myeloma cells. Our study revealed: (i) a dramatic induction of REDD1, a negative regulator of mammalian target of rapamycin kinase complex 1 (mTORC1) activity, in these cells; (ii) a transient cell size decrease associated with REDD1 overexpression; and (iii) partial restoration of bortezomib sensitivity in REDD1 knockdown bortezomib-resistant myeloma cells. Together, these results identify a possible novel mechanism of bortezomib resistance in myeloma patients mediated by REDD1 overexpression involving inhibition of mTORC1 activity and suggest that the use of mammalian target of rapamycin inhibitors in myeloma patients could be deleterious.
authors.affiliation: INSERM, U892, Université de Nantes, Nantes, France. olivier.decaux@chu-rennes.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Decaux
authors.forename: Monique
authors.initials: M
authors.lastname: Clément
authors.forename: Florence
authors.initials: F
authors.lastname: Magrangeas
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gouraud
authors.forename: Catherine
authors.initials: C
authors.lastname: Charbonnel
authors.forename: Loïc
authors.initials: L
authors.lastname: Campion
authors.forename: Hervé Avet
authors.initials: HA
authors.lastname: Loiseau
authors.forename: Stéphane
authors.initials: S
authors.lastname: Minvielle
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D048429:Cell Size; D003907:Dexamethasone / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011719:Pyrazines / Q000627:therapeutic use*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D001897:Boronic Acids; C500984:CRTC1 protein, human; C469991:DDIT4 protein, human; D011719:Pyrazines; D014157:Transcription Factors; D000069286:Bortezomib; D003907:Dexamethasone