Sammanfattning
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. [Figure not available: see fulltext.].
Originalspråk | Engelska |
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Artikelnummer | 42 |
Antal sidor | 12 |
Tidskrift | Oncogenesis |
Volym | 12 |
Nummer | 1 |
DOI | |
Status | Publicerad - 12 aug. 2023 |
MoE-publikationstyp | A1 Tidskriftsartikel-refererad |
Finansiering
This work was supported by grants from Academy of Finland, Finnish Medical Foundation, Finnish Cancer Foundations, Turku University Foundation, Turku University Hospital, TYKS Foundation, Finnish Cultural Foundation, and Turku Doctoral Programme of Molecular Medicine (TuDMM). We thank Zebrafish Core, Cell Imaging Core, Finnish Functional Genomics Centre, and Medical Bioinformatics Centre (all in Turku Bioscience Centre and supported by Biocenter Finland) for services, instrumentation, and consultations. We thank Sinikka Collanus and the Histology core facility of the Institute of Biomedicine, University of Turku, for their help with IHC. We thank Minna Santanen for excellent technical assistance. We thank Petra Sipilä for her help with ChIP-Seq analysis. The results included here include the use of data from The Metastatic Prostate Cancer Project (https://mpcproject.org/ ), a project of Count Me In (https://joincountmein.org/ ). The results published here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
Finansiärer | Finansiärsnummer |
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Finnish Cancer Foundations | |
Medical Bioinformatics Centre | |
Metastatic Prostate Cancer Project | |
Sinikka Collanus | |
Turku Doctoral Programme of Molecular Medicine, Turku, Finland. | |
Finnish Medical Foundation | |
Academy of Finland | |
Finska Kulturfonden | |
Åbo universitet | |
Turun Yliopistollisen Keskussairaalan Koulutus- ja Tutkimussäätiö | |
Turku University Hospital | |
Biocenter Finland |