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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer
1Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA. dpeehl@stanford.edu
Abstract:
A number of hormonal ligands and/or the nuclear receptors that mediate their actions have been targeted for prostate cancer therapy. Androgens, the ligands for the androgen receptor (AR), are critical for the growth of prostate cancer. Inhibition of androgen production has been the mainstay of treatment for advanced prostate cancer for decades. Other more recently tested targets include retinoid receptors (RAR and RXR), glucocorticoid receptors (GR), estrogen receptors (ER) and peroxisome proliferator-activated receptors (PPAR). Calcitriol, acting through the Vitamin D receptor (VDR), has many tumor suppressive activities in the prostate, including inhibition of proliferation, induction of apoptosis and/or differentiation, and reduction of cellular invasion. Because of these properties, calcitriol and its less hypercalcemic analogs are being evaluated as agents to prevent or treat prostate cancer. Androgens, retinoids, glucocorticoids, estrogens and agonists of PPAR directly or indirectly impact Vitamin D signaling pathways, and vice versa. In order to design the most effective strategies to use calcitriol to prevent or treat prostate cancer, the interactions of other nuclear receptors and their ligands with the Vitamin D signaling pathway need to be considered.
Insights
Vitamin D receptor (VDR) agonists like calcitriol show promise for prostate cancer treatment due to tumor-suppressive effects. Understanding interactions with other nuclear receptors is key for effective therapeutic strategies.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Hormonal ligands and nuclear receptors are key targets in prostate cancer therapy.
- Androgen receptor (AR) signaling is crucial for prostate cancer growth, with androgen deprivation therapy being a long-standing treatment.
- Other nuclear receptors like RAR, RXR, GR, ER, and PPAR are also investigated targets.
Purpose of the Study:
- To evaluate calcitriol (active Vitamin D) and its analogs for prostate cancer prevention and treatment.
- To explore the tumor-suppressive activities of calcitriol in prostate cancer, including proliferation inhibition, apoptosis induction, and reduced invasion.
- To investigate the complex interactions between the Vitamin D signaling pathway and other nuclear receptors (androgens, retinoids, glucocorticoids, estrogens, PPARs).
Main Methods:
- Review and analysis of existing research on nuclear receptor signaling in prostate cancer.
- Evaluation of calcitriol's known biological activities relevant to cancer suppression.
- Examination of cross-talk between Vitamin D receptor (VDR) and other nuclear receptors (AR, RAR, RXR, GR, ER, PPAR).
Main Results:
- Calcitriol exhibits significant tumor-suppressive activities in prostate cancer models.
- Androgens, retinoids, glucocorticoids, estrogens, and PPAR agonists influence VDR signaling pathways.
- Vitamin D signaling pathways reciprocally affect the action of these other nuclear receptors.
Conclusions:
- Calcitriol and its analogs hold potential as therapeutic agents for prostate cancer.
- Understanding the intricate interplay between VDR and other nuclear receptors is essential for optimizing calcitriol-based treatment strategies.
- Further research into these interactions will facilitate the design of more effective prostate cancer therapies.
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