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Decrease in the level and mRNA expression of LH-RH and EGF receptors after treatment with LH-RH antagonist cetrorelix
N Lamharzi1, G Halmos, A Jungwirth
1Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Department of Experimental Medicine, Tulane University School of Medicine, New Orleans, LA 70146, USA.
Abstract:
Using radioligand binding, RT-PCR, and Southern blot analyses, we evaluated whether agonist [D-Trp6]LH-RH and antagonist Cetrorelix could affect the levels of receptors for LH-RH and EGF and expression of mRNA for these receptors in DU-145 human androgen-independent prostate cancers xenografted into nude mice. Radioligand binding studies showed the presence of specific high affinity receptors for LH-RH and EGF in DU-145 prostate tumors. Cetrorelix, but not [D-Trp6]LH-RH significantly inhibited tumor growth. The concentration of LH-RH receptors was reduced by 22% (p<0. 05) and 67% (p<0.01) after 4 weeks of treatment with [D-Trp6]LH-RH and Cetrorelix respectively. The concentration of EGF receptors fell by 48% (p<0.05) in the [D-Trp6]LH-RH group, whereas Cetrorelix led to a 66% reduction (p<0.01). The expression of LH-RH and EGF receptor mRNA was investigated by RT-PCR analysis followed by Southern blotting. Densitometric analysis of the developed bands showed that the antagonist Cetrorelix decreased the expression of LH-RH receptor mRNA by 55% (p<0.01) compared to control group while the 20% reduction after treatment with the LH-RH agonist was non-significant. Treatment with [D-Trp6]LH-RH and Cetrorelix also reduced the expression of EGF receptor mRNA by 35% and 68% respectively (both, p<0.01) compared to control group. In conclusion, these data demonstrate that growth inhibition of DU-145 prostate tumors induced by prolonged administration of LH-RH antagonist Cetrorelix is accompanied by a marked decrease in the concentration of LH-RH and EGF receptors as well as in their mRNA levels.
Insights
The luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix significantly inhibited prostate tumor growth by reducing LH-RH and EGF receptor levels and mRNA expression. This suggests Cetrorelix as a potential therapeutic agent for prostate cancer.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Prostate cancer often exhibits dependence on androgen signaling pathways.
- Luteinizing hormone-releasing hormone (LH-RH) and epidermal growth factor (EGF) receptors are implicated in prostate cancer progression.
- Androgen-independent prostate cancer models, like DU-145 xenografts, are crucial for evaluating novel therapeutic strategies.
Purpose of the Study:
- To investigate the effects of an LH-RH agonist ([D-Trp6]LH-RH) and antagonist (Cetrorelix) on LH-RH and EGF receptor expression in DU-145 prostate cancer xenografts.
- To determine the impact of these treatments on tumor growth inhibition.
Main Methods:
- Xenograft model using DU-145 human androgen-independent prostate cancer in nude mice.
- Radioligand binding assays to quantify receptor concentrations.
- Reverse transcription-polymerase chain reaction (RT-PCR) and Southern blotting to assess mRNA expression levels.
Main Results:
- Cetrorelix significantly inhibited DU-145 tumor growth, while [D-Trp6]LH-RH did not.
- Both treatments reduced LH-RH and EGF receptor concentrations and mRNA expression, with Cetrorelix showing more pronounced effects.
- Cetrorelix decreased LH-RH receptor concentration by 67% and EGF receptor concentration by 66%.
Conclusions:
- LH-RH antagonist Cetrorelix effectively inhibits androgen-independent prostate cancer growth.
- The anti-tumor effect of Cetrorelix is associated with significant downregulation of both LH-RH and EGF receptor expression at the protein and mRNA levels.