title: Dinaciclib (SCH727965) inhibits the unfolded protein response through a CDK1- and 5-dependent mechanism.
abstract: Evidence implicating dysregulation of the IRE1/XBP-1s arm of the unfolded protein response (UPR) in cancer pathogenesis (e.g., multiple myeloma) has prompted the development of IRE1 RNase inhibitors. Here, effects of cyclin-dependent kinase (CDK) inhibitor SCH727965 (dinaciclib) on the IRE1 arm of the UPR were examined in human leukemia and myeloma cells. Exposure of cells to extremely low (e.g., nmol/L) concentrations of SCH727965, a potent inhibitor of CDKs 1/2/5/9, diminished XBP-1s and Grp78 induction by the endoplasmic reticulum (ER) stress-inducers thapsigargin and tunicamycin, while sharply inducing cell death. SCH727965, in contrast to IRE1 RNase inhibitors, inhibited the UPR in association with attenuation of XBP-1s nuclear localization and accumulation rather than transcription, translation, or XBP-1 splicing. Notably, in human leukemia cells, CDK1 and 5 short hairpin RNA (shRNA) knockdown diminished Grp78 and XBP-1s upregulation while increasing thapsigargin lethality, arguing for a functional role for CDK1/5 in activation of the cytoprotective IRE1/XBP-1s arm of the UPR. In contrast, CDK9 or 2 inhibitors or shRNA knockdown failed to downregulate XBP-1s or Grp78. Furthermore, IRE1, XBP-1, or Grp78 knockdown significantly increased thapsigargin lethality, as observed with CDK1/5 inhibition/knockdown. Finally, SCH727965 diminished myeloma cell growth in vivo in association with XBP-1s downregulation. Together, these findings demonstrate that SCH727965 acts at extremely low concentrations to attenuate XBP-1s nuclear accumulation and Grp78 upregulation in response to ER stress inducers. They also highlight a link between specific components of the cell-cycle regulatory apparatus (e.g., CDK1/5) and the cytoprotective IRE1/XBP-1s/Grp78 arm of the UPR that may be exploited therapeutically in UPR-driven malignancies.
authors.affiliation: Corresponding Author: Steven Grant, Massey Cancer Center, Virginia Commonwealth University, Room 234, 401 College Street, P.O. Box 980035, Richmond, VA 23298-0035. stgrant@vcu.edu.
authors.forename: Tri K
authors.initials: TK
authors.lastname: Nguyen
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007212:Indolizines; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011726:Pyridinium Compounds / Q000008:administration & dosage*; D012326:RNA Splicing / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000633:toxicity; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*; D000071717:X-Box Binding Protein 1
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007212:Indolizines; D011726:Pyridinium Compounds; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C553669:dinaciclib; D019284:Thapsigargin; D051360:Cyclin-Dependent Kinase 5; D016203:CDC2 Protein Kinase