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Glucocorticoid rece...
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Virtanen, Verneri
(author)
Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer.
- Article/chapterEnglish2023
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LIBRIS-ID:oai:gup.ub.gu.se/330426
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https://gup.ub.gu.se/publication/330426URI
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https://doi.org/10.1038/s41389-023-00485-zDOI
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Subject category:art swepub-publicationtype
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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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Paunu, Kreetta
(author)
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Kukkula, Antti
(author)
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Niva, Saana
(author)
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Junila, Ylva
(author)
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Toriseva, Mervi
(author)
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Jokilehto, Terhi
(author)
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Mäkelä, Sari
(author)
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Huhtaniemi, Riikka
(author)
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Poutanen, MattiGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Centre for Bone and Arthritis Research,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xpouma
(author)
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Paatero, Ilkka
(author)
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Sundvall, Maria
(author)
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Göteborgs universitetInstitutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition
(creator_code:org_t)
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Göteborgs universitet
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Gothenburg University
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Göteborgs universitet
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Gothenburg University
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In:Oncogenesis12:12157-9024
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Virtanen, Verner ...
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Paunu, Kreetta
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Kukkula, Antti
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Niva, Saana
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Junila, Ylva
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Toriseva, Mervi
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Jokilehto, Terhi
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Mäkelä, Sari
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Huhtaniemi, Riik ...
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Poutanen, Matti
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Paatero, Ilkka
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Sundvall, Maria
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- MEDICAL AND HEALTH SCIENCES
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Oncogenesis
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University of Gothenburg