title: The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4.
abstract: The proteasome inhibitor bortezomib has shown remarkable clinical success in the treatment of multiple myeloma. However, the efficacy and mechanism of action of bortezomib in solid tumor malignancies is less well understood. In addition, the use of this first-in-class proteasome inhibitor is limited by several factors, including off-target effects that lead to adverse toxicities. We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors. Both compounds promote upregulation of proapoptotic BIK and antiapoptotic MCL1, which serves to mediate and attenuate, respectively, the killing activities of these proteasome inhibitors. Both compounds also induce complete autophagic flux that is partially dependent on activation of the unfolded protein response (UPR) and upregulation of ATF4. Carfilzomib- and oprozomib-induced autophagy acts to promote HNSCC cell survival. Our study indicates that the therapeutic benefit of these promising proteasome inhibitors may be improved by inhibiting MCL1 expression or autophagy.
authors.affiliation: Department of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zang
authors.forename: Sufi M
authors.initials: SM
authors.lastname: Thomas
authors.forename: Elena T
authors.initials: ET
authors.lastname: Chan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kirk
authors.forename: Maria L
authors.initials: ML
authors.lastname: Freilino
authors.forename: Hannah M
authors.initials: HM
authors.lastname: DeLancey
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.forename: Changyou
authors.initials: C
authors.lastname: Li
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Johnson
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D000077195:Squamous Cell Carcinoma of Head and Neck; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D001897:Boronic Acids; C554738:ONX 0912; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D051701:Activating Transcription Factor 4; D000069286:Bortezomib; C524865:carfilzomib