Epidermal growth factor receptor is a cancer driver whose nuclear localization has been associated with the progression of prostate cancer to the castration-resistant phenotype. Previous reports indicated a functional interaction between this receptor and the protein Annexin A1, which has also been associated with aggressive tumors. The molecular pathogenesis of castration-resistant prostate cancer remains largely unresolved, and herein we have demonstrated the correlation between the expression levels and localization of the epidermal growth factor receptor and Annexin A1 in prostate cancer samples and cell lines. Interestingly, a higher expression of both proteins was detected in castration-resistant prostate cancer cell lines and the strongest correlation was seen at the nuclear level. We verified that Annexin A1 interacts with the epidermal growth factor receptor, and by using prostate cancer cell lines knocked down for Annexin A1, we succeeded in demonstrating that Annexin A1 promotes the nuclear localization of epidermal growth factor receptor. Finally, we showed that Annexin A1 activates an autocrine signaling in castration-resistant prostate cells through the formyl peptide receptor 1. The inhibition of such signaling by Cyclosporin H inhibits the nuclear localization of epidermal growth factor receptor and its downstream signaling. The present work sheds light on the functional interaction between nuclear epidermal growth factor receptor and nuclear Annexin A1 in castration-resistant prostate cancer. Therefore, strategies to inhibit the nuclear localization of epidermal growth factor receptor through the suppression of the Annexin A1 autocrine loop could represent an important intervention strategy for castration-resistant prostate cancer.

表皮生长因子受体是癌症驱动器，其核定位与前列腺癌向去势抵抗性表型的进展有关。先前的报道表明该受体与膜联蛋白A1之间的功能相互作用，该蛋白还与侵袭性肿瘤有关。去势抵抗性前列腺癌的分子发病机制仍未解决，在这里我们证明了前列腺癌样品和细胞系中表皮生长因子受体和膜联蛋白A1的表达水平与定位之间的相关性。有趣的是，在去势抵抗性前列腺癌细胞系中检测到了两种蛋白的更高表达，并且在核水平上发现了最强的相关性。我们验证了膜联蛋白A1与表皮生长因子受体相互作用，并且通过使用被击倒膜联蛋白A1的前列腺癌细胞系，我们成功地证明了膜联蛋白A1促进了表皮生长因子受体的核定位。最后，我们证明膜联蛋白A1通过甲酰肽受体1激活去势抵抗性前列腺细胞中的自分泌信号传导。环孢菌素H对这种信号传导的抑制作用抑制了表皮生长因子受体的核定位及其下游信号传导。本工作阐明了去势抵抗性前列腺癌中核表皮生长因子受体与核膜联蛋白A1之间的功能相互作用。因此，