PgmNr D1324: Novel inhibitor of cdk5 signaling axis suppresses self-renewal properties of glioblastoma stem cells and induces apoptosis.

Authors:
Subhas Mukherjee 1 ; Monica Chau 1 ; Carol Tucker-Burden 1 ; Changming Zhang 1 ; Jun Kong 2 ; Renee Read 1 ; Daniel Brat 1


Institutes
1) Emory University School of Medicine, Atlanta, GA; 2) Emory University, Atlanta, GA.


Keyword: cancer

Abstract:

Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal and multipotent differentiation. Growth is favored by deregulated stem cell division, which enhances the self-renewing population and diminishes the differentiation program. Mutation of a single gene Brain Tumor (brat) in Drosophila, leads to disrupted asymmetric cell division resulting in dramatic neoplastic proliferation of neuroblasts. To uncover mechanisms relevant to deregulated cell division in human glioma stem cells, we developed a novel adult Drosophila brain tumor model in which brat-RNAi is driven by the neuroblast specific promoter inscuteable. Suppressing Brat in this population led to accumulation of actively proliferating neuroblasts and a lethal brain tumor phenotype. brat-RNAi also caused Drosophila eye-overgrowth when driven by the eye-specific promoter ey-GAL4, providing a valuable screening phenotype. Cdk5 signaling is critical for neurogenesis and has been found to be hyperactive in neurodegenerative diseases. Paradoxically, many cancers also show abnormal activation of cdk5 signaling that drives uncontrolled proliferation, suggesting a unique therapeutic strategy where suppressing CDK5 can kill cancer cells and save dying neurons at the same time. In a screen of kinases that might oppose the actions of brat mutation on stem cell proliferation, we found that genetic suppression of Cdk5 in Drosophila partially reversed the eye over growth phenotype following Brat knock down. There is almost 79% identity between Drosophila Cdk5 and human CDK5. Additionally, IDH1 wild type glioblastomas in human show significant upregulation of CDK5 mRNA compared to its lower grade glioma counterparts. We translated our findings from Drosophila to patient-derived glioblastoma neurosphere cultures and in vivo xenograft tumors in mice, where we further demonstrated that a novel pharmaceutical suppressor of cdk5 signaling axis was capable of suppressing self-renewal properties and glioma stem cell viability by inducing apoptosis. Together, our results demonstrate a previously unappreciated role of the cdk5 signaling in glioma stem cell maintenance and survival and that suppressing cdk5 could be a novel therapeutic approach to specifically eliminate glioma stem cells.