Despite advances in diagnosis and treatment, prostate cancer is the most prevalent cancer in males and the second-highest cause of cancer-related mortality in men. We identified an RNA helicase gene, DDX3 (DDX3X), which is over-expressed in prostate cancers, and whose expression is directly correlated with high Gleason scores.
Knockdown of DDX3 in aggressive prostate cancer cell lines DU145 and 22Rv1 resulted in significantly reduced clonogenicity. To target DDX3, we rationally designed a small molecule, RK-33, which docks into the ATP-binding domain of DDX3. Functional studies indicated that RK-33 preferentially bound to DDX3 and perturbed its activity. Treatment of prostate cancer cell lines DU145, 22Rv1, and LNCaP (which have high DDX3 levels) with RK-33 decreased proliferation and induced a G1 phase cell cycle arrest. On the other hand, the low DDX3 expressing cell line, PC3, exhibited few changes following RK-33 treatment. Importantly, combination studies using RK-33 and radiation exhibited synergistic effects both in vitro and in a xenograft model of prostate cancer demonstrating the role of RK-33 as a radiosensitizer. Taken together, these results indicate that blocking DDX3 by RK-33 in combination with radiation treatment is a viable option for treating locally advanced prostate cancer.
Cancer research. 2016 Sep 12 [Epub ahead of print]
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Min Xie, Farhad Vesuna, Saritha Tantravedi, Guus M Bol, Marise R Heerma van Voss, Katriana Nugent, Reem Malek, Kathleen L Gabrielson, Paul J Van Diest, Phuoc T Tran, Venu Raman
Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine., Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine., Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions., Department of Pathology, University Medical Center Utrecht., Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine .