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TGF?-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells.

ABSTRACT: The Par complex - comprising partition-defective 6 (Par6), Par3, and atypical protein kinase C (aPKC) - is crucial for cell polarisation, the loss of which contributes to cancer progression. Transforming growth factor ? (TGF?)-induced phosphorylation of Par6 on the conserved serine 345 is implicated in epithelial-to-mesenchymal transition (EMT) in breast cancer. Here we investigated the importance of phosphorylated Par6 in prostate cancer.We generated a p-Par6(345)-specific antibody and verified its specificity in vitro. Endogenous p-Par6(345) was analysed by immunoblotting in normal human prostate RWPE1 and prostate cancer (PC-3U) cells. Subcellular localisation of p-Par6(345) in migrating TGF?-treated PC-3U cells was analysed by confocal imaging. Invasion assays of TGF?-treated PC-3U cells were performed. p-Par6 expression was immunohistochemically analysed in prostate cancer tissues.TGF? induced Par6 phosphorylation on Ser345 and its recruitment to the leading edge of the membrane ruffle in migrating PC-3U cells, where it colocalised with aPKC?. The p-Par6-aPKC? complex is important for cell migration and invasion, as interference with this complex prevented prostate cancer cell invasion. High levels of activated Par6 correlated with aggressive prostate cancer.Increased p-Par6Ser(345) levels in aggressive prostate cancer tissues and cells suggest that it could be a useful novel biomarker for predicting prostate cancer progression.

SUBMITTER: Mu Y

PROVIDER: S-EPMC4385960 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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TGFβ-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells.

Mu Y Y Zang G G Engström U U Busch C C Landström M M

British journal of cancer 20150331 7

<h4>Background</h4>The Par complex - comprising partition-defective 6 (Par6), Par3, and atypical protein kinase C (aPKC) - is crucial for cell polarisation, the loss of which contributes to cancer progression. Transforming growth factor β (TGFβ)-induced phosphorylation of Par6 on the conserved serine 345 is implicated in epithelial-to-mesenchymal transition (EMT) in breast cancer. Here we investigated the importance of phosphorylated Par6 in prostate cancer.<h4>Methods</h4>We generated a p-Par6( ...[more]

PMID: 25756394

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Project description:BackgroundProstate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression.MethodsImmunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot.ResultsIn prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn't affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines.ConclusionFRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation.

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TGF?-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells.

Publications

TGFβ-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells.

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