Inhibition of Atypical Protein Kinase C‑ι Effectively Reduces the Malignancy of Prostate Cancer cells by Downregulating the NF-κB Signaling Cascade

Authors

André H. Apostolatos, University of South Florida
Wishrawana Sarathi Bandara Ratnayake, University of South FloridaFollow
Hla Win-Piazza, University of South Florida
Christopher A. Apostolatos, University of South FloridaFollow
Tracess Smalley, University of South FloridaFollow
Loveleen Kang, University of South FloridaFollow
Raoul Salup, University of South Florida
Robert Hill, University of South Florida
Mildred Acevedo-Duncan, University of South FloridaFollow

Document Type

Article

Publication Date

2018

Keywords

protein kinase C-ι, atypical protein kinase C inhibitors, prostate cancer, nuclear factor-κB, biomarkers

Digital Object Identifier (DOI)

https://doi.org/10.3892/ijo.2018.4542

Abstract

Prostate cancer (PC) is the most common type of cancer among men. Aggressive and metastatic PC results in lifethreatening tumors, and represents one of the leading causes of mortality in men. Previous studies of atypical protein kinase C isoforms (aPKCs) have highlighted its role in the survival of cultured prostate cells via the nuclear factor (NF)-κB pathway. The present study showed that PKC-ι was overexpressed in PC samples collected from cancer patients but not in non-invasive prostate tissues, indicating PKC-ι as a possible prognostic biomarker for the progression of prostate carcinogenesis. Immunohistochemical staining further confirmed the association between PKC-ι and the prostate malignancy. The DU-145 and PC-3 PC cell lines, and the non-neoplastic RWPE-1 prostatic epithelial cell line were cultured and treated with aPKC inhibitors 2-acetyl-1,3-cyclopentanedione (ACPD) and 5-amino-1-(1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1). Western blot data demonstrated that ICA‑1 was an effective and specific inhibitor of PKC‑ι and that ACPD inhibited PKC-ι and PKC-ζ. Furthermore, the two inhibitors significantly decreased malignant cell proliferation and induced apoptosis. The inhibitors showed no significant cytotoxicity towards the RWPE-1 cells, but exhibited cytostatic effects on the DU-145 and PC-3 cells prior to inducing apoptosis. The inhibition of aPKCs significantly reduced the translocation of NF-κB to the nucleus. Furthermore, this inhibition promoted apoptosis, reduced signaling for cell survival, and reduced the proliferation of PC cells, whereas the normal prostate epithelial cells were relatively unaffected. Overall, the results suggested that PKC-ι and PKC-ζ are essential for the progression of PC, and that ACPD and ICA-1 can be effectively used as potential inhibitors in targeted therapy.

Rights Information

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

International Journal of Oncology, v. 53, p. 1836-1846

Scholar Commons Citation

Apostolatos, André H.; Ratnayake, Wishrawana Sarathi Bandara; Win-Piazza, Hla; Apostolatos, Christopher A.; Smalley, Tracess; Kang, Loveleen; Salup, Raoul; Hill, Robert; and Acevedo-Duncan, Mildred, "Inhibition of Atypical Protein Kinase C‑ι Effectively Reduces the Malignancy of Prostate Cancer cells by Downregulating the NF-κB Signaling Cascade" (2018). Chemistry Faculty Publications. 71.
https://digitalcommons.usf.edu/chm_facpub/71