致命前列腺癌（PCa）的特点是存在转移并对治疗产生抵抗。转移是通过动态细胞骨架重塑的多步骤过程形成的. 一种调节肌动蛋白细胞骨架的基因，CALD1，编码一个卡尔德蒙蛋白（CaD）。它的同工酶，低分子量CaD（l-CaD），在非肌肉细胞中发挥作用，支持与力量产生和力学感知有关的丝状物的功能。已经确定几个因素，包括糖皮质激素受体（GR），在不同细胞类型中调节l-CaD的作用，但是在PCa中l-CaD的调节尚未确定。PCa在对雄激素信号进行治疗抑制后以多种策略产生抵抗。已知的策略包括雄激素受体（AR）的改变，改变类固醇合成，并绕过AR信号传导，例如通过GR上调。在这里，我们报告了体外下调l-CaD促进上皮表型，并减少3D中的球体生长，这在斑马鱼PCa异种移植模型中反映为原位形成转移的减少。相应地，CALD1 mRNA表达与PCa患者中的上皮间质转化（EMT）转录本相关。我们还展示了CALD1与GR在多个PCa数据集中高度共表达，并且GR的激活在体外上调l-CaD。此外，GR的上调与PCa异种移植小鼠模型中抗雄激素治疗抵抗发展后增加的l-CaD表达相关。总结一下，GR调节的l-CaD在PCa转移中发挥作用，当通过GR上调绕过AR信号传导以达到抗雄激素抵抗时具有临床相关性。©2023. 汤森路透美国国家公司

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.© 2023. Springer Nature America, Inc.