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Targeting DDX3 with a small molecule inhibitor for lung cancer therapy.

Bol GM, Vesuna F, Xie M, Zeng J, Aziz K, Gandhi N, Levine A, Irving A, Korz D, Tantravedi S, Heerma van Voss MR, Gabrielson K, Bordt EA, Polster BM, Cope L, van der Groep P, Kondaskar A, Rudek MA, Hosmane RS, van der Wall E, van Diest PJ, Tran PT, Raman V - EMBO Mol Med (2015)

Bottom Line: We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity.Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-β-catenin axis and inhibited non-homologous end joining-the major DNA repair pathway in mammalian somatic cells.Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

No MeSH data available.


Related in: MedlinePlus

Bioinformatics analysis of DDX3 knockdown and RK-33 treatmentA Scatter plot of the gene expression log2 fold change in DDX3 knockdown and RK-33-treated MDA-MB-231 cells. Each red dot represents a gene, which was significantly perturbed after treatment with RK-33 and after knockdown of DDX3.B The Venn diagram depicts the number of common genes dysregulated by both shDDX3 and RK-33 treatments.C, D BioCarta pathway analysis of gene expression in DDX3 knockdown and RK-33-treated cells. Pathways are ranked on LS permutation P-values from top to bottom.
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fig03: Bioinformatics analysis of DDX3 knockdown and RK-33 treatmentA Scatter plot of the gene expression log2 fold change in DDX3 knockdown and RK-33-treated MDA-MB-231 cells. Each red dot represents a gene, which was significantly perturbed after treatment with RK-33 and after knockdown of DDX3.B The Venn diagram depicts the number of common genes dysregulated by both shDDX3 and RK-33 treatments.C, D BioCarta pathway analysis of gene expression in DDX3 knockdown and RK-33-treated cells. Pathways are ranked on LS permutation P-values from top to bottom.

Mentions: To confirm the inhibition of DDX3 by RK-33 and determine specificity, we measured gene expression in MDA-MB-231 cells by microarray analysis after treatment of RK-33 or knockdown of DDX3. As shown in Fig3A, gene expression changes of RK-33-treated cells correlated with DDX3 knockdown cells (rho = 0.673, using genes altered in both classes at P < 0.005). This is supported by a Venn diagram displaying the overlap of gene expression between shDDX3- and RK-33-treated cells (Fig3B). This indicates that the functional activity of RK-33 is via DDX3 inhibition and that it could be used as a small molecule inhibitor of DDX3.


Targeting DDX3 with a small molecule inhibitor for lung cancer therapy.

Bol GM, Vesuna F, Xie M, Zeng J, Aziz K, Gandhi N, Levine A, Irving A, Korz D, Tantravedi S, Heerma van Voss MR, Gabrielson K, Bordt EA, Polster BM, Cope L, van der Groep P, Kondaskar A, Rudek MA, Hosmane RS, van der Wall E, van Diest PJ, Tran PT, Raman V - EMBO Mol Med (2015)

Bioinformatics analysis of DDX3 knockdown and RK-33 treatmentA Scatter plot of the gene expression log2 fold change in DDX3 knockdown and RK-33-treated MDA-MB-231 cells. Each red dot represents a gene, which was significantly perturbed after treatment with RK-33 and after knockdown of DDX3.B The Venn diagram depicts the number of common genes dysregulated by both shDDX3 and RK-33 treatments.C, D BioCarta pathway analysis of gene expression in DDX3 knockdown and RK-33-treated cells. Pathways are ranked on LS permutation P-values from top to bottom.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492822&req=5

fig03: Bioinformatics analysis of DDX3 knockdown and RK-33 treatmentA Scatter plot of the gene expression log2 fold change in DDX3 knockdown and RK-33-treated MDA-MB-231 cells. Each red dot represents a gene, which was significantly perturbed after treatment with RK-33 and after knockdown of DDX3.B The Venn diagram depicts the number of common genes dysregulated by both shDDX3 and RK-33 treatments.C, D BioCarta pathway analysis of gene expression in DDX3 knockdown and RK-33-treated cells. Pathways are ranked on LS permutation P-values from top to bottom.
Mentions: To confirm the inhibition of DDX3 by RK-33 and determine specificity, we measured gene expression in MDA-MB-231 cells by microarray analysis after treatment of RK-33 or knockdown of DDX3. As shown in Fig3A, gene expression changes of RK-33-treated cells correlated with DDX3 knockdown cells (rho = 0.673, using genes altered in both classes at P < 0.005). This is supported by a Venn diagram displaying the overlap of gene expression between shDDX3- and RK-33-treated cells (Fig3B). This indicates that the functional activity of RK-33 is via DDX3 inhibition and that it could be used as a small molecule inhibitor of DDX3.

Bottom Line: We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity.Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-β-catenin axis and inhibited non-homologous end joining-the major DNA repair pathway in mammalian somatic cells.Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

No MeSH data available.


Related in: MedlinePlus