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Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate
Indira Elangovan1, Sivasakthivel Thirugnanam, Aoshuang Chen
1Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL 61107, USA.
Abstract:
Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.
Insights
Silencing the receptor for advanced glycation end products (RAGE) using RNA interference inhibits prostate cancer cell growth and triggers apoptosis. This approach also reduced tumor growth in vivo, suggesting RAGE as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Receptor for advanced glycation end products (RAGE) is implicated in prostate cancer progression.
- The therapeutic value of targeting RAGE in prostate cancer remains largely unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of silencing RAGE expression via RNA interference (RNAi) in prostate cancer.
- To evaluate the in vitro and in vivo efficacy of RAGE-targeted RNAi.
Main Methods:
- Utilized RNAi to downregulate RAGE expression in both androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cell lines.
- Assessed the impact of RAGE silencing on cell proliferation, apoptosis (caspase-8 and caspase-3 activation), and prostate-specific antigen (PSA) levels.
- Administered RAGE RNAi constructs in a xenograft mouse model of prostate cancer to evaluate in vivo tumor growth inhibition.
Main Results:
- RAGE downregulation via RNAi significantly inhibited proliferation in LNCaP and DU-145 prostate cancer cells.
- Targeting RAGE induced apoptosis through the activation of caspase-8 and caspase-3 signaling pathways.
- RAGE RNAi reduced PSA levels in LNCaP cells and suppressed tumor growth in vivo by modulating RAGE, HMGB1, and death receptor (DR4, DR5) expression.
Conclusions:
- Silencing RAGE expression through RNAi demonstrates significant anti-proliferative and pro-apoptotic effects on prostate cancer cells.
- RAGE-targeted RNAi therapy shows promise in inhibiting prostate cancer progression and tumor growth.
- Targeting RAGE represents a potential novel therapeutic strategy for prostate cancer treatment.
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