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.
Highlights
In 2019, it is estimated that ∼1.7 million new incidences of cancer will be diagnosed and 600,000 cancer deaths will occur [1]
The results demonstrated that the top mutations in ovarian cancer overall are TP53 (p53), FOXL2 (Forkhead box protein L2), KRAS (Kirsten Ras oncogene homolog), PIK3CA
The search was refocused to only contain clear cell ovarian carcinoma (CCOC) samples and the top two mutated genes found were PIK3CA (33%) and ARID1A (50%) (Table 2). These results suggest that one of the most common gene mutations in ovarian cancer and CCOC is PIK3CA, which is ∼10% of mutated samples in all the ovarian tissue in the database
Summary
In 2019, it is estimated that ∼1.7 million new incidences of cancer will be diagnosed and 600,000 cancer deaths will occur [1]. Ovarian cancer is estimated to reach 22,530 diagnoses and cause 13,980 cancer deaths per year [1]. This constitutes 5% of cancer deaths among women and is responsible for being the most lethal gynecological cancer diagnosis [3]. The most common ovarian cancer diagnosis is epithelial ovarian carcinomas (EOC), which constitutes 85–90% of diagnosis [3]. Of this percent, clear cell ovarian carcinoma (CCOC)
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