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

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