Dinaciclib is a member of a class of drugs known as cyclin-dependent kinase (CDK) inhibitors. CDKs regulate a series of events known as the cell cycle, or cell-division cycle, that lead to the division and duplication of cells. In many cancers, CDKs are overactive or CDK-inhibiting proteins are not functional, which results in the unregulated proliferation of cancer cells. Laboratory observations from this study suggest that two specific CDKs, CDK1 and CDK5, play key roles in regulating the UPR by helping to control the production and accumulation of a protein known as X-box binding pretein-1 (XBP-1).
The spliced form of XBP-1 (XBP-1s) helps regulate the expression of genes critical to cellular stress responses. External stressors, including certain anti-cancer agents, can cause mis-folded proteins to accumulate in the endoplasmic reticulum (ER), an interconnected network of sacs and tubules that manufacture, process and transport a variety of compounds important for cell survival. These stressors can also cause XBP-1s to accumulate in the cell’s nucleus, which promotes the UPR and helps cells withstand the damaging effects of mis-folded proteins. The scientists discovered that dinaciclib, by interfering with UPR activation, caused multiple myeloma and myeloid leukemia cells to initiate a form of cell suicide known as apoptosis when exposed to agents that induced ER stress.
“These findings build on a long history of work in our laboratory investigating mechanisms by which cancer cells respond to environmental stresses,” Grant said. “We intend to continue investigating ways in which dinaciclib and other CDK inhibitors might be used to disrupt the UPR and potentially improve the effectiveness of certain agents for the treatment of multiple myeloma or myeloid leukemia.”
Grant collaborated with Tri Nguyen, Ph.D., instructor in the Department of Internal Medicine at the VCU School of Medicine, who spearheaded this study.
This study was supported by awards CA93738, CA100866, CA167708, RC2CA148431 and R21CA137823 from the National Institutes of Health (NIH); award 6238-12 from the Leukemia and Lymphoma Society of America; Myeloma SPORE award CA142509; Lymphoma SPORE award 1P50 CA130805from the NIH; the Multiple Myeloma Research Foundation; and, in part, by funding from VCU Massey Cancer Center’s NIH-NCI Cancer Center Support Grant P30 CA016059. Microscopy was performed at the VCU School of Medicine Department of Neurobiology and Anatomy microscopy facility, which is supported, in part, by NIH-NINDS center core grant 5P30NS047463.
The full manuscript of the study is available online at: http://mct.aacrjournals.org/content/early/2013/12/20/1535-7163.MCT-13-0714.full.pdf+html
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