CDK5 inhibition suppresses glioma stem cell self-renewal

View:383 Time:2018-05-15

Glioblastoma is a fast-growing, aggressive type of tumor that grows from the supportive tissue of the brain. Prognosis of the disease is very poor that even with optimal therapy, survival is usually only about 12 to 15 months. The short survival time of glioblastoma is associated with its high recurrence rate, which is attributed to the presence of a critical glioblastoma subpopulation, known as glioma stem cells (GSCs). So many studies in this field are aimed to uncover mechanisms and potential therapeutic targets in tumor stem cell self-renewal.

Now, researchers from Northwestern University used Drosophilabrain tumor models to discover that an enzyme called CDK5 plays a substantial role in the regulation of GSCs. The study also tested an experimental inhibitor of CDK5 and found it effective in suppressing GSC self-renewal and reducing tumor growth. The findings, detailed in a paper titled “CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells” in the journal Cell Reports, suggests that CDK5 inhibition could curb glioblastoma growth through eliminating CDK5-dependent GSCs.

CDK5, short for Cyclin-dependent kinase 5, is also called cell division protein kinase 5. It's a member of the cyclin-dependent kinase (CDK) family, enzymes that modify other proteins by chemically adding phosphate groups. CDKs were first discovered for their role in regulating the cell cycle and now many other functions of these enzymes have been well established, such as modulating transcription, mRNA processing, and differentiation of neurons.

CDK5 plays a role in proper neurodevelopment and functions as a switch between neuronal survival and death. Previous studies have suggested that overactivation of CDK5 is implicated in various neurodegenerative disorders. Recent evidence indicates that CDK5 is also involved glioblastoma.

In the current study, the researchers carried out a genetic suppressor screen on their Drosophila brain tumor model. They discovered that when the gene encoding CDK5 was silenced, tumor burden decreased and cancer stem cells reduced. Patient data revealed that CDK5 is frequently amplified in glioblastoma (83%). CDK5 was found to promote stemness. Cells that were most stem-like contained more CDK5 than cells that were less stem-like. The researchers also tested an experimental CDK5 inhibitor, CP681301, and found that it stopped tumor growth and reduced cancer stem cell self-renewal.

These data indicate that CDK5 is critical to GSCs and glioblastoma recurrence. Thus, drugs that inhibit CDK5 may be a way to treat forms of glioblastoma that highly express CDK5.
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