Abstract

Atypical protein kinase C (aPKC) are involved in cellular survival, differentiation, and metastasis of many human cancers. Epithelial to mesenchymal transition (EMT) is an important process in tumor progression that converts stationary epithelial cells into motile mesenchymal cells by expressing Vimentin. Molecular dynamics of Vimentin intermediate filaments (VIFs) depend on phosphorylation through various kinases; play several key roles in cancer metastasis. Prognosis of mesenchymal prostate malignancies is low, offers only meek capacity to mitigate metastasis and also impedes insight into molecular mechanisms that drive the metastasis of prostate cancer cells. Recently, we reported that aPKCs induce survival and differentiation of metastatic prostate cancer cell lines by activating the AKT/NF-κB pathway. This article is an effort to provide thorough understanding of the relationship between Vimentin and aPKCs (in-vitro and in-vivo) established on aPKC specific inhibitors. We demonstrate that diminution of aPKCs lead to attenuate prostate cellular migration and invasion through the downregulation of Vimentin expression. siRNA knocked-down SNAIL1 and PRRX1 reduce aPKC activity along with Vimentin. Results suggest that aPKCs target multiple activation sites (Ser33, Ser39 and Ser56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells. Understanding the aPKC related molecular mechanisms may provide a novel therapeutic path for prostate carcinoma.

摘要

非典型蛋白激酶C（aPKC）参与许多人类癌症的细胞存活，分化和转移。上皮向间充质转化（EMT）是肿瘤进展中的重要过程，其通过表达波形蛋白将固定的上皮细胞转化为能动的间充质细胞。波形蛋白中间丝（VIF）的分子动力学取决于各种激酶的磷酸化作用。在癌症转移中起着关键作用。间充质前列腺恶性肿瘤的预后很低，仅能柔和地减轻转移，也妨碍了对驱动前列腺癌细胞转移的分子机制的了解。最近，我们报道了aPKCs通过激活AKT /NF-κB途径诱导转移性前列腺癌细胞系的存活和分化。体外和体内（aPKC特异性抑制剂）。我们证明减少aPKCs导致通过波形蛋白表达的下调来减弱前列腺细胞的迁移和侵袭。si RNA抑制的SNAIL1和PRRX1与波形蛋白一起降低aPKC活性。结果表明，aPKCs靶向波形蛋白上的多个激活位点（Ser33，Ser39和Ser56），因此对于前列腺癌细胞转移过程中的VIF动态调节至关重要。了解与aPKC相关的分子机制可能为前列腺癌提供一种新颖的治疗途径。