Dinaciclib (SCH727965) inhibits the unfolded protein response through a CDK1- and 5-dependent mechanism
1Corresponding 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.
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.
Insights
The cyclin-dependent kinase inhibitor SCH727965 effectively targets the unfolded protein response (UPR) pathway in leukemia and myeloma cells. This drug reduces cancer cell growth by inhibiting XBP-1s nuclear accumulation, offering a potential therapeutic strategy for UPR-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Stress Response
Background:
- Dysregulation of the IRE1/XBP-1s arm of the unfolded protein response (UPR) is implicated in cancer pathogenesis, particularly multiple myeloma.
- This has led to the development of IRE1 RNase inhibitors as a therapeutic strategy.
- The role of cyclin-dependent kinases (CDKs) in this pathway remains to be fully elucidated.
Purpose of the Study:
- To investigate the effects of the CDK inhibitor SCH727965 on the IRE1/XBP-1s arm of the UPR in human leukemia and myeloma cells.
- To determine the mechanism by which SCH727965 affects UPR signaling and cell viability.
- To explore the potential therapeutic implications of targeting CDK/UPR interactions in UPR-driven malignancies.
Main Methods:
- Treatment of human leukemia and myeloma cells with SCH727965 at low concentrations.
- Assessment of XBP-1s and Grp78 induction by endoplasmic reticulum (ER) stress inducers (thapsigargin, tunicamycin).
- Evaluation of cell death, XBP-1s nuclear localization, and protein accumulation.
- Short hairpin RNA (shRNA) knockdown of specific CDKs (1, 2, 5, 9) and UPR components (IRE1, XBP-1, Grp78).
- In vivo studies using SCH727965 in a myeloma xenograft model.
Main Results:
- SCH727965 (dinaciclib), a potent inhibitor of CDKs 1/2/5/9, significantly reduced XBP-1s and Grp78 induction by ER stress inducers at nanomolar concentrations.
- SCH727965 induced cell death and inhibited the UPR by attenuating XBP-1s nuclear localization and accumulation, distinct from IRE1 RNase inhibitors.
- CDK1 and CDK5 knockdown mimicked SCH727965 effects, reducing Grp78 and XBP-1s and increasing thapsigargin-induced lethality, suggesting a role for CDK1/5 in UPR activation.
- Knockdown of IRE1, XBP-1, or Grp78 increased thapsigargin lethality, similar to CDK1/5 inhibition.
- SCH727965 reduced myeloma tumor growth in vivo, correlating with XBP-1s downregulation.
Conclusions:
- SCH727965 effectively attenuates XBP-1s nuclear accumulation and Grp78 upregulation in response to ER stress at very low concentrations.
- A functional link exists between cell-cycle regulators CDK1/5 and the cytoprotective IRE1/XBP-1s/Grp78 pathway of the UPR.
- This CDK-UPR axis represents a potential therapeutic target for malignancies driven by UPR dysregulation.
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