c‑Jun and FOXO1 mediate the expression of oncogenic PKC‑&iota; in human prostate cancer cells with an interplay between NF‑&kappa;B, IL‑8 and ICAM‑1

Ratnayake,Wishrawana S.; Apostolatos,Christopher A.; Breedy,Sloan; Acevedo-Duncan,Mildred

doi:10.3892/wasj.2020.57

c‑Jun and FOXO1 mediate the expression of oncogenic PKC‑ι in human prostate cancer cells with an interplay between NF‑κB, IL‑8 and ICAM‑1

Authors:
- Wishrawana S. Ratnayake
- Christopher A. Apostolatos
- Sloan Breedy
- Mildred Acevedo-Duncan
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Affiliations: Department of Chemistry, University of South Florida, Tampa, FL 33620, USA
Published online on: June 23, 2020 https://doi.org/10.3892/wasj.2020.57
Article Number: 16
Copyright: © Ratnayake et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Aggressive and metastatic prostate cancers are among the leading causes of fatality in men. Prior observations by the authors regarding atypical protein kinase C isoforms (aPKCs) in relation to prostate cancers demonstrated elevated levels of PKC‑iota (PKC‑ι) in patient samples compared to non‑malignant prostate tissues. This indicates that PKC‑ι is a potential biomarker for initiating and maintaining prostate carcinogenesis. In addition, PKC‑ι is an oncogene that encourages the activation of the nuclear factor (NF)‑κB, assisting carcinogenesis. The specific inhibition of PKC‑ι de‑regulated the expression of both PKC‑ι and its phosphorylation; thus, PKC‑ι functionally controls its own expression in prostate carcinoma. The present study aimed to investigate the underlying mechanisms of PRKCI gene transcriptional regulation in prostate carcinoma cells. Forkhead box protein O1 (FOXO1) and c‑Jun, along with several other transcription factors that exhibited potential to bind on or near the promoter region of the PRKCI were identified. Each transcription factor was systematically silenced. The decrease in the expression levels of FOXO1 and c‑Jun significantly affected PKC‑ι expression. The decrease in FOXO1 expression by siRNA enhanced PKC‑ι expression by 33% (P≤0.05) and 9% (P≤0.05) in the PC‑3 and DU‑145 cells, respectively. The diminution of c‑Jun expression by siRNA diminished PKC‑ι expression by 42% (P≤0.05) and 24% (P≤0.05) in the PC‑3 and DU‑145 cells, respectively. According to the results of the present study, c‑Jun and FOXO1 are the two major transcription factors involved in PKC‑ι expression in prostate cells. PKC‑ι and its phosphorylation improved due to FOXO1 diminution, and vice versa for c‑Jun silencing, indicating that c‑Jun upregulates PRKCI expression, while FOXO1 negatively affects its expression. This was mediated through signal transducer and activator of transcription (STAT)3/5 and NF‑κB. An upregulation in the expression of intercellular adhesion molecule 1 (ICAM‑1) and interleukin (IL)‑8 was observed as a result of PKC‑ι specific inhibition. PKC‑ι inhibition thus promotes ICAM‑1/FOXO1 signaling and downregulates IL‑8/JNK/c‑Jun signaling, indicating that PKC‑ι inhibition subdues its production mechanism. Overall, an analysis of the results led us to suggest that PKC‑ι inhibition downregulates its own oncogenic signaling, while the induction of anti‑tumor signaling pathways strongly suggests that PKC‑ι related molecular mechanisms provide a novel therapeutic route for mitigating prostate cancer.

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