Protein Kinase C-ζ stimulates colorectal cancer cell carcinogenesis via PKC-ζ/Rac1/Pak1/β-Catenin signaling cascade

Abstract

Colorectal cancer (CRC) is the second most common cancer in the world and death from CRC accounts for 8% of all cancer deaths both in men and women in the United States. CRC is life-threatening disease due to therapy resistant cancerous cells. The exact mechanisms of cell growth, survival, metastasis and inter & intracellular signaling pathways involved in CRC is still a significant challenge. Hence, investigating the signaling pathways that lead to colon carcinogenesis may give insight into the therapeutic target. In this study, the role of atypical Protein Kinase C (aPKC) on CRC was investigated by using two inhibitors of that protein class: 1) ζ-Stat (8-hydroxynaphthalene-1,3,6-trisulfonic acid) is a specific inhibitor of PKC-ζ and 2) ICA-I 5-amino-1-(2,3-dihydroxy-4-hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide) is a specific inhibitor of PKC-ι. The cell lines tested were CCD18CO normal colon epithelial and LOVO metastatic CRC cells. The inhibition of aPKCs did not bring any significant toxicity on CCD18CO normal colon cell line. Although PKC-ι is an oncogene in many cancers, we found the overexpression of PKC-ζ and its direct association with Rac1. Our findings suggest that the PKC-ζ may be responsible for the abnormal growth, proliferation, and migration of metastatic LOVO colon cancer cells via PKC-ζ/Rac1/Pak1/β-Catenin pathway. These results suggest the possibility of utilizing PKC-ζ inhibitor to block CRC cells growth, proliferation, and metastasis.

Defining the relevant combinatorial space of the PKC/CARD-CC signal transduction nodes

“…The surprising dependency of CBM complexes downstream of the atypical PKCs further expands the potential use of CBM-interfering interventions as a therapeutic strategy. For example, the PKCζ NF-κB → pathway has been found to be important in cardiac hypertrophy, prostate-and colorectal cancer [88][89][90]. PKCι/λ has also been shown to act as an oncogene in many different types of cancer [90,91].…”

Simultaneous inhibition of atypical protein kinase‑C and mTOR impedes bladder cancer cell progression

“…Immunoprecipitation (IP). Protein (3 µg) was immunoprecipitated from 300 µg protein containing cell lysate suspension using primary antibody of interest and separated by SDS-PAGE and finally analyzed using the western blotting technique to determine the associated proteins with the IP protein as described in our previous study (8).…”

“…Activation of conventional PKCs (α, β1, β2 and γ) depends on diacylglycerol and Ca 2+ , whereas novel PKCs (θ, δ, η and ε) are activated by diacylglycerol. However, atypical PKCs (ι and ζ) require neither diacylglycerol, nor calcium, instead they require protein-protein interaction (8). PKCs are involved in various cell signaling events that stimulate cell growth, proliferation, apoptosis, metastasis and regulation of gene expression (9).…”

“…Protein kinases, specifically atypical PKCs, have been implicated in numerous types of cancer, such as breast cancer, colon cancer, melanoma, ovarian cancer and glioblastoma (8,9,(17)(18)(19)(20). Additionally, unlike other PKCs, atypical PKC has a glutamic acid at the HM region, which makes the TM of the atypical PKC sensitive to mTOR-mediated phosphorylation and stabilization of PKC-ι and PKC-ζ (14).…”

The Atypical Protein Kinase C Small Molecule Inhibitor ζ-Stat, and Its Effects on Invasion Through Decreases in PKC-ζ Protein Expression

“…The upregulation of this pathway increases the expression of downstream survival targets (e.g., PKC-ζ). PKC-ζ has been shown to be involved in tumorigenesis, tissue invasion, and cancer progression through the modulation of cell migration machinery, such as Ras Homolog Family Member A (RhoA), Rac Family Small GTPase 1 (Rac1), and Epithelial Cell Transforming 2 (Ect2) (14)(15)(16).…”