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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation
Daniel E Frigo1, Donald P McDonnell
1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
Androgen ablation therapy is widely used for the treatment of advanced prostate cancer. However, the effectiveness of this intervention strategy is generally short-lived as the disease ultimately progresses to a hormone-refractory state. In recent years, it has become clear that even in antiandrogen-resistant cancers the androgen receptor (AR) signaling axis is intact and is required for prostate cancer growth. Thus, there is a heightened interest in developing small molecules that function in part by down-regulating AR expression in tumors. Paradoxically, AR expression has been shown to be important in preventing the transdifferentiation of epithelial prostate cancer cells toward a neuroendocrine phenotype associated with tumor progression. Consequently, we have evaluated the relative effect of prostate cancer therapeutics that function in part by depleting AR levels on neuroendocrine differentiation in established cellular models of prostate cancer. These studies reveal that although histone deacetylase inhibitors can down-regulate AR expression they increase the expression of neuroendocrine markers and alter cellular morphology. Inhibition of AR signaling using classic AR antagonists or small interfering RNA-mediated AR ablation induces incomplete neuroendocrine differentiation. Importantly, the Hsp90 inhibitor geldanamycin effectively down-regulates AR expression while having no effect on neuroendocrine differentiation. Taken together, these data show that the phenotypic responses to pharmacologic agents used in the clinic to prevent the progression of prostate cancer are not equivalent, a finding of significant therapeutic importance.
Insights
Androgen ablation therapy for prostate cancer can lead to resistance. Some treatments that lower androgen receptor (AR) levels may worsen neuroendocrine differentiation, but Hsp90 inhibitors like geldanamycin do not.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Androgen ablation therapy is a primary treatment for advanced prostate cancer, but often leads to hormone-refractory disease.
- The androgen receptor (AR) signaling pathway remains crucial for cancer growth, even in resistant forms.
- AR expression is also vital in preventing prostate cancer cell transdifferentiation into a neuroendocrine phenotype linked to progression.
Purpose of the Study:
- To evaluate the impact of prostate cancer therapeutics that deplete AR levels on neuroendocrine differentiation.
- To compare the effects of different therapeutic strategies on AR expression and neuroendocrine markers in prostate cancer models.
Main Methods:
- Utilized established cellular models of prostate cancer.
- Assessed the effects of histone deacetylase inhibitors, AR antagonists, small interfering RNA (siRNA)-mediated AR ablation, and the Hsp90 inhibitor geldanamycin.
- Monitored changes in AR expression, neuroendocrine markers, and cellular morphology.
Main Results:
- Histone deacetylase inhibitors reduced AR expression but increased neuroendocrine markers and altered cell morphology.
- AR signaling inhibition via antagonists or siRNA resulted in incomplete neuroendocrine differentiation.
- Geldanamycin effectively downregulated AR expression without impacting neuroendocrine differentiation.
Conclusions:
- Different therapeutic agents targeting AR signaling have distinct effects on neuroendocrine differentiation in prostate cancer.
- Hsp90 inhibition represents a promising strategy, downregulating AR without inducing adverse neuroendocrine changes.
- Therapeutic choices significantly influence cellular phenotype, highlighting the importance of considering these effects in clinical practice.
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