Plakophilin 1 deficiency in prostatic tumours is correlated with immune cell recruitment and controls the up‐regulation of cytokine expression post‐transcriptionally

Abstract

Plakophilin (PKP1) 1 is a member of the arm‐repeat family of catenins and acts as a structural component of desmosomes, which are important stabilizers of cell–cell adhesion. Besides this, PKP1 also occurs in a non‐junctional, cytoplasmic form contributing to post‐transcriptional regulation of gene expression. Moreover, PKP1 is expressed in the prostate epithelium but its expression is frequently downregulated in prostate cancers with a more aggressive phenotype. This observation may imply a tumour‐suppressive role of PKP1. We found that, in prostatic adenocarcinomas with PKP1 deficiency, the occurrence of T‐cells, B‐cells, macrophages and neutrophils were significantly increased. In a PKP1‐deficient prostatic cancer cell line expressing IL8, these levels were statistically meaningfully reduced upon PKP1 re‐expression. When analysing prostatic PKP1 knockdown cell lines, the mRNA and protein levels of additional cytokines, namely CXCL1 and IL6, were upregulated. The effect was rescued upon re‐expression of a PKP1 RNAi‐resistant form. The corresponding mRNAs were co‐precipitated with cytoplasmic PKP1, indicating that they are components of PKP1‐containing mRNA ribonucleoprotein particles. Moreover, the mRNA half‐lives of CXCL1, IL8 and IL6 were significantly increased in PKP1‐deficient cells, showing that these mRNAs were stabilized by PKP1. In an in vitro migration assay, the higher cytokine concentrations led to higher migration rates of THP1 and PBMC cells. This finding implies that PKP1 loss of expression in vivo correlates with the recruitment of immune cells into the tumour area to set up a tumour‐specific environment. One may speculate that this newly established tumour environment has tumour‐suppressive characteristics and thereby accelerates tumour progression and metastasis.

Evaluation of the Clinical Application Value of Cytokine Expression Profiles in the Differential Diagnosis of Prostate Cancer

“…This nding is consistent with previous studies that reported increased IL-6 levels in the peripheral blood of prostate cancer patients [28][29][30]. IL-6 is known to play a critical role in prostate-mediated immune responses and can stimulate humoral and cellular immune responses by acting on B and T lymphocytes, promoting their growth and differentiation, and participating in in ammation induced by follicular Th cells [27,28,31].…”

“…Paul Katongole and others also found increased IL-6 levels in the serum of prostate cancer patients [26]. These cytokines are mainly secreted by T and B lymphocytes and are important components of the immune response, playing important roles in various biological functions, including immune response against bacterial infections [27]. These results indicate that in ammation often occurs during the evolution of prostate cancer and these indicators may be essential in diagnosing the disease.…”

Unveiling the Binding between the Armadillo-Repeat Domain of Plakophilin 1 and the Intrinsically Disordered Transcriptional Repressor RYBP

“…In general terms, RYBP expression appears to be downregulated in those cancer types, and low RYBP expression is associated with poor prognosis [77,82,84,85]. On the other hand, PKP1 appears implicated in the development of prostate, lung, and breast cancers, among others [35,38,39,46,73,86]. Based on these data, we hypothesized that PKP1 and RYBP could interact directly with each other, at least in some of those cancer cell lines.…”

“…We have recently shown that PADI4 binds to ARM-PKP1 [54] and RYBP [33]. Furthermore, both proteins are implicated in the progression of several cancer types [18,38,46,73,74], and they can act as oncogenes or tumor suppressors. In fact, several studies have shown that the expression of RYBP is dysregulated in various human tumor tissues, including prostate [75,76], lung [77], liver, breast, hepatocellular carcinoma, glioblastoma [78], Hodgkin lymphoma, and cervical cancer [17,19,[79][80][81][82][83].…”

The role of proinflammatory cytokines and CXC chemokines (CXCL1–CXCL16) in the progression of prostate cancer: insights on their therapeutic management

“…PKP1 depletion in vivo recruits immune cells to create a tumor-specific milieu. This new cancer environment may be tumor suppressive, accelerating tumor growth and progression [ 161 ].…”