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

Abstract

Ovarian cancer is estimated to reach 22,530 diagnoses and cause 13,980 cancer deaths per year. The most common histology diagnosed of ovarian cancer is epithelial ovarian carcinomas (EOC). An aggressive epithelial subtype is clear cell ovarian carcinoma (CCOC) and is characterized as a non-serous ovarian cancer. Protein kinase C (PKC) is an enzymatic family of proteins that have been found to be a component in cancer progression, tissue invasion, and metastasis. The atypical PKC (aPKC) isoforms, PKC-ι and PKC-ζ, have been suggested to participate in the increased proliferation of ovarian cancers. Previous studies have indicated that novel aPKC inhibitors ICA-1S and ζ-Stat decreased the migratory behaviors of colorectal cancer cells and were selective for PKC-ι/λ and PKC-ζ, respectively. The aims of this investigation were to further determine the binding mechanisms of ζ-Stat, expand on the tissue range of these compounds, investigate the therapeutic potential of ζ-Stat in CCOC, and to illustrate the disruption of invasion via the PKC-ζ signaling cascade. The methods utilized were molecular docking and virtual target screening, Western blot analysis, end-point PCR, GST pull down, cell viability and invasion and migration assays. We discovered that the small molecule inhibitor, ζ-Stat, is a prospective drug candidate to investigate as a novel potential treatment for CCOC. We also found that the PKC-ζ/Ect2/Rac1 activation pathway was decreased by ζ-Stat, which in turn decreased invasive behavior of CCOC.

Multifractality in Surface Potential for Cancer Diagnosis

“…The previous study showed an overexpression of PKC proteins in ES-2 cells compared to SHT290 cells, utilizing Ca 2+ in a complex signaling cascade involved in cancer progression . Although the comparison of the SHT290 and ES-2 is not a standard cancer model, previous work established the differences between the surfaces of the SHT290 and ES-2 cells with relevance to cancer progression by investigating the mechanism of cancer treatment by the inhibition of the PKC protein expression . Using this model allows us to correlate the changes in the multifractality of the surface potential with the expression of PKC proteins that are different in these cell lines.…”

“…Different media compositions provide varying amounts of nutrients, growth factors, and other essential components for cell growth and maintenance that can influence cell metabolism, membrane composition, and overall cell behavior . We used the same growth media that were previously used for the comparison of the SHT290 and ES-2 cells …”

“…54,55 PKC activation by Ca 2+ may reflect the change in the surface potential, although binding of PKC to the inner side of the plasma membrane does not affect the membrane's outer surface morphology. 55 The previous study showed an overexpression of PKC proteins in ES-2 cells compared to SHT290 cells, 55 utilizing Ca 2+ in a complex signaling cascade involved in cancer progression. 56 Although the comparison of the SHT290 and ES-2 is not a standard cancer model, previous work established the differences between the surfaces of the SHT290 and ES-2 cells with relevance to cancer progression by investigating the mechanism of cancer treatment by the inhibition of the PKC protein expression.…”

6,6′-Dihydroxythiobinupharidine (DTBN) Purified from Nuphar lutea Leaves Is an Inhibitor of Protein Kinase C Catalytic Activity

“…Sitemap score is based on the potential hydrogen bonding, hydrophobicity, and pocket volume. A site score greater than 0.9 is considered as a cut-off to distinguish between the potential drug binding site and non-drug binding sites [ 39 ]. The site-score and predicted residues involved in the ATP binding pocket of PKC isoforms are given in Table 6 .…”

Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

“…In ovarian cancer, PKCζ has proapoptotic functions and participates in cell invasion and migration. The PKCζ inhibitor ζ-Stat decreased the invasive behavior of ovarian cancer cells by decreasing the activation of cytosolic Ect2 and Rac1 [ 234 ].…”