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REIC/Dkk-3 as a potential gene therapeutic agent against human testicular cancer
Ryuta Tanimoto1, Fernando Abarzua, Masakiyo Sakaguchi
1Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Abstract:
Human testicular cancer is very sensitive to chemotherapy and radiation therapy and is regarded as a curable cancer. The cancer prevails in the young reproductive generation and testicular dysfunction is often observed as a side effect, remaining a serious challenge. In the present study, we examined the potential utility of REIC/Dkk-3-based gene therapy against human testicular cancer. Expression of REIC/Dkk-3 was reduced in all of the human seminoma and non-seminomatous germ cell tumor tissues. Overexpression of REIC/Dkk-3 using an adenovirus vector (Ad-REIC) induced apoptosis in a testicular germ cell cancer cell line NCCIT but not in normal human fibroblasts. c-Jun terminal kinase (JNK) was activated by Ad-REIC and the induction of apoptosis was abrogated by a JNK inhibitor. A single intratumoral injection of Ad-REIC markedly inhibited the tumorigenic growth of NCCIT cells in nude mice. These results indicate that Ad-REIC may lead to developing less insulting and non-genotoxic therapeutic measures against human testicular cancer.
Insights
Gene therapy using REIC/Dkk-3 shows promise for treating human testicular cancer. This novel approach, delivered via adenovirus vector (Ad-REIC), effectively targets cancer cells while sparing normal cells, offering a less toxic treatment option.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Human testicular cancer is highly curable but often causes testicular dysfunction in young patients.
- Current treatments like chemotherapy and radiation can lead to long-term side effects.
- There is a need for less toxic and non-genotoxic therapeutic strategies.
Purpose of the Study:
- To investigate the potential of REIC/Dkk-3 gene therapy for human testicular cancer.
- To evaluate the efficacy and safety of an adenovirus vector expressing REIC/Dkk-3 (Ad-REIC).
Main Methods:
- Examined REIC/Dkk-3 expression in human testicular tumor tissues.
- Overexpressed REIC/Dkk-3 using Ad-REIC in a testicular cancer cell line (NCCIT).
- Assessed apoptosis induction, c-Jun terminal kinase (JNK) activation, and tumor growth inhibition in vivo.
Main Results:
- REIC/Dkk-3 expression was reduced in human seminoma and non-seminoma tissues.
- Ad-REIC induced apoptosis in NCCIT cells but not in normal fibroblasts.
- Ad-REIC activated JNK, and apoptosis was blocked by a JNK inhibitor.
- Intratumoral Ad-REIC injection inhibited tumor growth in nude mice.
Conclusions:
- REIC/Dkk-3 gene therapy, delivered by Ad-REIC, demonstrates significant anti-cancer activity against testicular germ cell tumors.
- Ad-REIC induces cancer cell apoptosis via JNK activation.
- Ad-REIC represents a promising, less insulting, and non-genotoxic therapeutic strategy for testicular cancer.
