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Updated: Aug 9, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 19, 2013
Lyn is a target gene for prostate cancer: sequence-based inhibition induces regression of human tumor xenografts
Mirela Goldenberg-Furmanov1, Ilan Stein, Eli Pikarsky
1Department of Experimental Medicine and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Abstract:
The Src-related protein kinase Lyn plays an important role in B-cell activation. However, several lines of evidence suggest that it is also involved in the control of cellular proliferation and the inhibition of apoptosis. We have discovered that Lyn is expressed in normal prostate epithelia, in 95% of primary human prostate cancer (PC) specimens examined, and in all of the PC cell lines that we assayed. Moreover, Lyn knockout mice display abnormal prostate gland morphogenesis, which suggests that Lyn plays an important role in prostate epithelium development and implies that Lyn is a candidate target for specific therapy for PC. Using a drug-design strategy to construct sequence-based peptide inhibitors, a Lyn-specific inhibitor, KRX-123, targeting a unique interaction site within Lyn, was synthesized. KRX-123 was found to inhibit cellular proliferation in three hormone-refractory PC cell lines, DU145, PC3, and TSU-Pr1 with IC(50) values of 2-4 micro M. In vivo, tumor volume of DU145 explants in nude mice was significantly reduced after once-a-week injections of KRX-123, at a dose of 10 mg/kg, for a period of 5 weeks. Histological analyses of the treated tumors indicated extensive apoptosis. Thus, we suggest that Lyn inhibition may serve as a prime target for the treatment of hormone-refractory PC.
Insights
The protein kinase Lyn is found in prostate cancer and drives tumor growth. A new inhibitor, KRX-123, effectively reduced tumor size and increased cell death in preclinical models, suggesting Lyn as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The Src-related protein kinase Lyn is implicated in B-cell activation, cellular proliferation, and apoptosis inhibition.
- Lyn is expressed in normal prostate epithelia and frequently detected in human prostate cancer (PC) tissues and cell lines.
Purpose of the Study:
- To investigate the role of Lyn in prostate cancer development and progression.
- To evaluate Lyn as a therapeutic target for hormone-refractory PC.
- To assess the efficacy of a novel Lyn-specific inhibitor, KRX-123.
Main Methods:
- Expression analysis of Lyn in prostate tissues and cell lines.
- Generation and testing of Lyn knockout mice for prostate gland development.
- Synthesis of a Lyn-specific peptide inhibitor (KRX-123) using a drug-design strategy.
- In vitro assessment of KRX-123's effect on PC cell proliferation.
- In vivo evaluation of KRX-123's anti-tumor activity in a mouse xenograft model.
Main Results:
- Lyn is expressed in normal prostate epithelia and highly prevalent in prostate cancer.
- Lyn knockout mice exhibit abnormal prostate gland morphogenesis, indicating its developmental role.
- KRX-123 inhibited proliferation in hormone-refractory PC cell lines (DU145, PC3, TSU-Pr1) with IC(50) values of 2-4 µM.
- In vivo, KRX-123 treatment significantly reduced DU145 tumor volume in mice and induced extensive apoptosis.
Conclusions:
- Lyn plays a significant role in prostate epithelium development and cancer progression.
- Lyn is a promising therapeutic target for hormone-refractory prostate cancer.
- Lyn inhibition via agents like KRX-123 demonstrates potential for PC treatment.
