{"title":"Investigating the contribution of the unfolded protein response to prostate cancer bone metastasis","authors":"Z. Kaya","doi":"10.37707/jnds.v2i4.208","DOIUrl":null,"url":null,"abstract":"Zeynep Kaya, John C. Christianson, Ian G. Mills, Srinivasa R. Rao, Claire M. Edwards \n \nThe majority of deaths from PCa arise following metastasis, particularly to the skeleton. ER stress and the unfolded protein response (UPR) promote primary PCa, however the contribution of the UPR to PCa bone metastasis remains unknown. The aim of this work was to determine the role of the UPR in PCa bone metastasis, focusing on the osteogenic potential of PCa cells, EMT and migration, and PCa-induced bone disease. Using paired cell lines ARCaPE and ARCaPM which differ in their epithelial (E) and mesenchymal (M) characteristics, we found that components of IRE1 and ATF6 pathways are higher in ARCaPE cells than in ARCaPM and decreased upon osteogenic differentiation of ARCaPM cells. Inhibition of the IRE1 or PERK pathway increased ALP activity in ARCaPM cells. Inhibition of specific arms of the UPR produced a varied response in EMT markers with no effect on migration of ARCaPM cells. Increasing ER stress using tunicamycin significantly reduced migration of ARCaPM cells. The bone disease associated with PCa bone metastases is driven by alterations in a complex signaling network, including the RANKL/OPG pathway and Wnt signaling. ER stress, induced by tunicamycin, decreased RANKL and Dkk1 expression and increased OPG expression in ARCaPM cells. This osteolytic response to ER stress was blocked by PERK inhibition. Taken together, my research demonstrates that the UPR has multiple effects in bone metastatic PCa cells, including a reduction in migration and in osteolytic factors following UPR activation, suggesting a novel mechanism by which the UPR may modulate PCa-induced bone disease.","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"20 1","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the Nuffield Department of Surgical Sciences","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.37707/jnds.v2i4.208","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Zeynep Kaya, John C. Christianson, Ian G. Mills, Srinivasa R. Rao, Claire M. Edwards
The majority of deaths from PCa arise following metastasis, particularly to the skeleton. ER stress and the unfolded protein response (UPR) promote primary PCa, however the contribution of the UPR to PCa bone metastasis remains unknown. The aim of this work was to determine the role of the UPR in PCa bone metastasis, focusing on the osteogenic potential of PCa cells, EMT and migration, and PCa-induced bone disease. Using paired cell lines ARCaPE and ARCaPM which differ in their epithelial (E) and mesenchymal (M) characteristics, we found that components of IRE1 and ATF6 pathways are higher in ARCaPE cells than in ARCaPM and decreased upon osteogenic differentiation of ARCaPM cells. Inhibition of the IRE1 or PERK pathway increased ALP activity in ARCaPM cells. Inhibition of specific arms of the UPR produced a varied response in EMT markers with no effect on migration of ARCaPM cells. Increasing ER stress using tunicamycin significantly reduced migration of ARCaPM cells. The bone disease associated with PCa bone metastases is driven by alterations in a complex signaling network, including the RANKL/OPG pathway and Wnt signaling. ER stress, induced by tunicamycin, decreased RANKL and Dkk1 expression and increased OPG expression in ARCaPM cells. This osteolytic response to ER stress was blocked by PERK inhibition. Taken together, my research demonstrates that the UPR has multiple effects in bone metastatic PCa cells, including a reduction in migration and in osteolytic factors following UPR activation, suggesting a novel mechanism by which the UPR may modulate PCa-induced bone disease.
Zeynep Kaya, John C. Christianson, Ian G. Mills, Srinivasa R. Rao, Claire M. Edwards,大多数前列腺癌的死亡发生在转移后,特别是转移到骨骼。内质网应激和未折叠蛋白反应(UPR)促进原发性前列腺癌,但UPR对前列腺癌骨转移的贡献尚不清楚。这项工作的目的是确定UPR在PCa骨转移中的作用,重点关注PCa细胞的成骨潜能、EMT和迁移以及PCa诱导的骨病。利用上皮细胞(E)和间充质细胞(M)特征不同的配对细胞系ARCaPE和ARCaPM,我们发现ARCaPE细胞中的IRE1和ATF6通路成分高于ARCaPM细胞,并在ARCaPM细胞成骨分化时降低。抑制IRE1或PERK通路可增加ARCaPM细胞的ALP活性。抑制UPR的特定臂在EMT标记物中产生不同的反应,但对ARCaPM细胞的迁移没有影响。tunicamycin增加内质网应激可显著降低ARCaPM细胞的迁移。与PCa骨转移相关的骨病是由一个复杂信号网络的改变驱动的,包括RANKL/OPG通路和Wnt信号。tunicamycin诱导的内质网应激降低了ARCaPM细胞中RANKL和Dkk1的表达,增加了OPG的表达。这种内质网应激的溶骨反应被PERK抑制所阻断。综上所述,我的研究表明,UPR对骨转移性PCa细胞有多种影响,包括在UPR激活后减少迁移和溶骨因子,这表明UPR可能调节PCa诱导的骨病的新机制。