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Updated: Mar 15, 2026
Laser-capture Microdissection of Human Prostatic Epithelium for RNA Analysis
Published on: November 26, 2015
RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3
Min Xie1, Farhad Vesuna1, Saritha Tantravedi1
1Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Abstract:
Despite advances in diagnosis and treatment, prostate cancer is the most prevalent cancer in males and the second highest cause of cancer-related mortality. We identified an RNA helicase gene, DDX3 (DDX3X), which is overexpressed in prostate cancers, and whose expression is directly correlated with high Gleason scores. Knockdown of DDX3 in the 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. RK-33 treatment of prostate cancer cell lines DU145, 22Rv1, and LNCaP (which have high DDX3 levels) decreased proliferation and induced a G1 phase cell-cycle arrest. Conversely, 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 Res; 76(21); 6340-50. ©2016 AACR.
Insights
Researchers identified DDX3 (DDX3X) as a target in prostate cancer. A novel molecule, RK-33, targeting DDX3, showed promise in combination with radiation therapy for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer remains a leading cause of cancer mortality in males.
- Overexpression of RNA helicase DDX3 (DDX3X) correlates with higher Gleason scores in prostate cancer.
Purpose of the Study:
- To investigate the role of DDX3 in prostate cancer progression.
- To develop and evaluate a small molecule inhibitor of DDX3, RK-33, as a potential therapeutic agent.
Main Methods:
- DDX3 expression analysis in prostate cancer tissues.
- Knockdown studies in prostate cancer cell lines (DU145, 22Rv1).
- Design and synthesis of RK-33, a DDX3-targeting molecule.
- In vitro studies assessing RK-33's effect on cell proliferation, cell cycle, and radiosensitization.
- In vivo studies using a prostate cancer xenograft model.
Main Results:
- DDX3 knockdown reduced clonogenicity in aggressive prostate cancer cells.
- RK-33 selectively inhibited DDX3 activity, decreased proliferation, and induced G1 cell-cycle arrest in high DDX3-expressing cell lines.
- RK-33 demonstrated minimal effects on low DDX3-expressing cells.
- Combination therapy with RK-33 and radiation showed synergistic effects in vitro and in vivo.
Conclusions:
- Targeting DDX3 with RK-33 is a promising strategy for prostate cancer treatment.
- RK-33 acts as a radiosensitizer, enhancing the efficacy of radiation therapy.
- The combination of RK-33 and radiation offers a viable treatment option for locally advanced prostate cancer.
