Colorectal cancer (CRC) is the second most common cancer in the world and death from colorectal cancer 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 colon cancer are still a major challenge for scientists. 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 colon cancer was identified by using four inhibitors of that particular protein class: 1) ACPD (2-acetyl-1,3-cyclopentanedione and 2) DNDA (3,4-diamino-2,7 naphthalenedisulfonic acid) are non-specific inhibitors of aPKCs; 3) ζ-Stat (8-hydroxy-1, 3, 6-naphthalenetrisulfonic acid) is a specific inhibitor of PKC-ζ; and 4) ICA-I (4, 5-amino-4-carbamoylimidazol-1-yl-2, 3-dihydroxycyclopentyl) methyl dihydrogen phosphate) is a specific inhibitor of PKC-ι. The cell lines tested were HT-29 colon cancer and CCD18CO normal colon epithelial. Although PKC-ι is an oncogene in many cancers, we found that the PKC-ζ was responsible for the abnormal growth and proliferation in HT-29 colon cancer cells. Additionally, the inhibition of aPKCs did not bring any significant toxicity on CCD18CO normal colon cell line. These results suggest the potentiality of utilizing aPKC-ζ inhibitors to block colon cancer cell growth and proliferation. Citation Format: S M Anisul Islam, Mildred Acevedo Duncan. The role of atypical protein kinase C in colorectal cancer cell growth and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5744. doi:10.1158/1538-7445.AM2017-5744
Βackground: β-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the production of Aβ-peptides that form Aβ-plaque in Alzheimer’s disease. Methods: Reportedly, acute insulin treatment in normal mice, and hyperinsulinemia in high-fat-fed (HFF) obese/diabetic mice, increase BACE1 activity and levels of Aβ-peptides and phospho- -thr-231-tau in the brain; moreover, these effects are blocked by PKC-λ/ι inhibitors. However, as chemical inhibitors may affect unsuspected targets, we presently used knockout methodology to further examine PKC-λ/ι requirements. We found that total-body heterozygous PKC-λ knockout reduced acute stimulatory effects of insulin and chronic effects of hyperinsulinemia in HFF/obese/diabetic mice, on brain PKC-λ activity and production of Aβ1-40/42 and phospho-thr-231-tau. This protection in HFF mice may reflect that hepatic PKC-λ haploinsufficiency prevents the development of glucose intolerance and hyperinsulinemia. Results: On the other hand, heterozygous knockout of PKC-λ markedly reduced brain levels of BACE1 protein and mRNA, and this may reflect diminished activation of nuclear factor kappa-B (NFκB), which is activated by PKC-λ and increases BACE1 and proinflammatory cytokine transcription. Accordingly, whereas intravenous administration of aPKC inhibitor diminished aPKC activity and BACE1 levels by 50% in the brain and 90% in the liver, nasally-administered inhibitor reduced aPKC activity and BACE1 mRNA and protein levels by 50-70% in the brain while sparing the liver. Additionally, 24-hour insulin treatment in cultured human-derived neurons increased NFκB activity and BACE1 levels, and these effects were blocked by various PKC-λ/ι inhibitors. Conclusion: PKC-λ/ι controls NFκB activity and BACE1 expression; PKC-λ/ι inhibitors may be used nasally to target brain PKC-λ/ι or systemically to block both liver and brain PKC-λ/ι, to regulate NFκB-dependent BACE1 and proinflammatory cytokine expression.
Lung cancer is the second most common cancer and it is the leading cause of cancer death in both men and women. PKC isozymes play an important role in the development and progression of many cancers by regulating the cell cycle, survival, apoptosis, cell motility and malignant transformation. Our focus is to study the role of atypical PKCs (aPKC) in cell proliferation and migration in lung cancer cell lines. We used a novel non-specific inhibitor of aPKC namely DNDA (3,4-amino-2,7napthalenedisulfonic acid). Our hypothesis is that DNDA inhibits cell proliferation and migration of lung cancer cells. Our data from cell viability and flow cytometry showed significant reduction in cell proliferation and induction of apoptosis with DNDA (10µM) in A549 and H1299 lung cancer cells. Additionally, DNDA showed no toxic effect on BEAS-2B normal lung cells. Elevated levels of Focal Adhesion kinase (FAK) are implicated in the progression of cancer and plays a vital role in the invasion and migration of cancer cells. Western blot results showed that the phosphorylation of PKC-ι and phosphorylation of FAK were decreased in A549 lung cancer cells upon DNDA treatment. Moreover, there was no significant reduction in phosphorylation of FAK in H1299 lung cancer cells upon treatment with DNDA. Immunoprecipitation (IP) data revealed an association of PKC-ι with FAK and FAK with Cbl-b. Ubitest results suggests that PKC-ι regulates the cleavage of FAK through its ubiquination by cbl-b and thus inhibits the migration of A549 lung cancer cells which was evident from scratch assay. Our data indicates that DNDA might inhibit the migration of A549 lung cancer cells by PKC-ι/FAK ubiquination via Cbl-b. Citation Format: Raja Reddy Bommareddy, Rekha Patel, Mildred Acevedo Duncan. Effects of atypical protein Kinase c inhibitor (DNDA) on lung cancer proliferation and migration by PKC-ι/FAK ubiquination through the Cbl-b pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4437.
It is estimated that in 2015 breast cancer will be the second leading cause of cancer death in women. For this purpose, biochemical markers for breast cancer have been investigated, to assist in early detection and more accurate diagnoses. In breast cancer tissue, the atypical isozyme of protein kinase C zeta, PKC-ζ, has been a topic in research; It has been shown that an overexpression of this protein may be indicative of developing carcinogenesis and contributes to proliferation through the NF kappa B pathway, which is a stress-regulated switch for cell survival. In this investigation, the expression of PKC-ζ was analyzed in normal and malignant female human breast tissue samples by Western blot, immunoprecipitation and PCR. In the preliminary results, the malignant breast tissue samples illustrated a significant expression of PKC ζ when compared to the expression of PKC-ζ in normal breast tissue samples. The same tissues were also processed for total RNA isolation which was followed by cDNA synthesis and Real Time PCR. The level of PKC-ζ mRNA was tested and no overexpression was observed in either malignant or normal breast tissue samples. While protein studies may suggest that PKC-ζ could be considered a biomarker for breast cancer, the same cannot be said about mRNA levels. The overexpression of PKC-ζ protein level and the normal PKC-ζ mRNA level are indicators of possible miRNA activity that may regulate translation in malignant tissues but not the normal. Citation Format: Christopher Apostolatos, Tracess Smalley, Mildred A. Duncan. Analysis of PKC-ζ protein and mRNA levels in normal and malignant breast tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3934.
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