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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth
Aleksandra Fesiuk1,2, Daniel Pölöske1,3, Elvin D de Araujo4,5
1Department of Pathology, Medical University of Vienna, Vienna, Austria.
Abstract:
Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent studies have identified THs as drivers of prostate cancer (PCa) development and progression. We reported that the T3-scavenger protein µ-crystallin (CRYM) regulates the development and progression of PCa and that this involved crosstalk with androgen receptor (AR) signaling. However, the mechanisms remain incompletely understood. Here, we explored the role of thyroid hormone receptor β (TRβ), which is the main effector of TH signaling, in the context of PCa. The use of the TRβ-selective antagonist NH-3 inhibited PCa cell proliferation in vitro and reduced tumor size in PCa xenograft models in vivo. Notably, NH-3 was highly effective in the engrafted 22Rv1 cell line, a model for castration-resistant PCa (CRPC). Mechanistic studies revealed that NH-3 downregulates AR and the AR target genes Nkx3.1 and KLK3 (PSA). NH-3 was a more effective anticancer agent than enzalutamide, and their combined use was synergistic. Evidence from human datasets corroborates our findings, whereby elevated TRβ expression and mutations in the TH signaling pathway are associated with the onset of PCa. Collectively, these results establish TRβ as a mediator of tumorigenesis in PCa and identify NH-3 as a promising therapeutic agent for targeting AR signaling, particularly in CRPC.
Insights
Thyroid hormone receptor beta (TRβ) drives prostate cancer (PCa) progression. A TRβ antagonist, NH-3, effectively inhibited PCa growth and androgen receptor signaling, showing promise for castration-resistant PCa treatment.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Thyroid hormone (TH) signaling influences tissue homeostasis and metabolism.
- Recent research implicates THs in prostate cancer (PCa) development and progression.
- µ-crystallin (CRYM) has been identified as a T3-scavenger protein involved in PCa and androgen receptor (AR) signaling crosstalk.
Purpose of the Study:
- To investigate the role of thyroid hormone receptor beta (TRβ), the primary TH signaling effector, in PCa.
- To evaluate the therapeutic potential of the TRβ-selective antagonist NH-3 in PCa models.
Main Methods:
- In vitro proliferation assays using PCa cell lines.
- In vivo studies using PCa xenograft models.
- Mechanistic investigations into AR and AR target gene regulation.
- Comparative efficacy analysis against enzalutamide.
- Analysis of human PCa datasets for TRβ expression and mutations.
Main Results:
- TRβ antagonism with NH-3 inhibited PCa cell proliferation and reduced tumor size in vivo.
- NH-3 demonstrated significant efficacy in castration-resistant PCa (CRPC) models (22Rv1 cell line).
- NH-3 downregulated AR and its target genes, including Nkx3.1 and KLK3 (PSA).
- NH-3 exhibited superior efficacy to enzalutamide, with synergistic effects when combined.
- Elevated TRβ expression and TH pathway mutations correlate with PCa onset in human data.
Conclusions:
- TRβ acts as a key mediator in PCa tumorigenesis.
- NH-3 is a potent therapeutic agent for PCa, particularly effective in targeting AR signaling in CRPC.
- TRβ antagonism represents a promising therapeutic strategy for advanced prostate cancer.
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