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Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer. | LitMetric

Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer.

Oncogenesis

Cancer Research Unit, Institute of Biomedicine, and FICAN West Cancer Center Laboratory, University of Turku, and Turku University Hospital, Kiinamyllynkatu 10, 20520, Turku, Finland.

Published: August 2023

AI Article Synopsis

  • * Research indicates that lowering levels of l-CaD can help maintain an epithelial cell structure and reduce the growth of cancer cell clusters, leading to fewer metastases in studies using zebrafish models.
  • * The study also found a strong connection between l-CaD and the glucocorticoid receptor (GR), showing that GR can enhance l-CaD levels, especially in contexts where prostate cancer develops resistance to common antiandrogen therapies.

Article Abstract

Lethal prostate cancer (PCa) is characterized by the presence of metastases and development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. Here, we report that in vitro downregulation of l-CaD promotes epithelial phenotype and reduces spheroid growth in 3D, which is reflected in vivo in reduced formation of metastases in zebrafish PCa xenografts. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition (EMT) transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets, and GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10423232PMC
http://dx.doi.org/10.1038/s41389-023-00485-zDOI Listing

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