title: miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1.
abstract: MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells.
authors.affiliation: Medical Oncology, Department of Experimental and Clinical Medicine, Magna Graecia University and T Campanella Cancer Center, Salvatore Venuta Campus, Catanzaro, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Amodio
authors.forename: M T
authors.initials: MT
authors.lastname: Di Martino
authors.forename: U
authors.initials: U
authors.lastname: Foresta
authors.forename: E
authors.initials: E
authors.lastname: Leone
authors.forename: M
authors.initials: M
authors.lastname: Lionetti
authors.forename: M
authors.initials: M
authors.lastname: Leotta
authors.forename: A M
authors.initials: AM
authors.lastname: Gullà
authors.forename: M R
authors.initials: MR
authors.lastname: Pitari
authors.forename: F
authors.initials: F
authors.lastname: Conforti
authors.forename: M
authors.initials: M
authors.lastname: Rossi
authors.forename: V
authors.initials: V
authors.lastname: Agosti
authors.forename: M
authors.initials: M
authors.lastname: Fulciniti
authors.forename: G
authors.initials: G
authors.lastname: Misso
authors.forename: F
authors.initials: F
authors.lastname: Morabito
authors.forename: M
authors.initials: M
authors.lastname: Ferrarini
authors.forename: A
authors.initials: A
authors.lastname: Neri
authors.forename: M
authors.initials: M
authors.lastname: Caraglia
authors.forename: N C
authors.initials: NC
authors.lastname: Munshi
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.forename: P
authors.initials: P
authors.lastname: Tagliaferri
authors.forename: P
authors.initials: P
authors.lastname: Tassone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D015536:Down-Regulation; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011719:Pyrazines / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D001897:Boronic Acids; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D011719:Pyrazines; D016329:Sp1 Transcription Factor; D000069286:Bortezomib