Atypical Protein Kinase Cs in Melanoma Progression

Melanoma is one of the fastest growing types of cancer worldwide in terms of incidence. To date, reports show over 92,000 new cases in the United States in 2018. Previously, we introduced protein kinase C-iota (PKC-ι) as an oncogene in melanoma. PKC-ι promotes survival and cancer progression along with PKC-zeta(ζ). In addition, we reported that PKC-ι induced metastasis of melanoma cells by increasing Vimentin dynamics. Our previous results showed that PKC-ι inhibition downregulated epithelial-mesenchymal transition (EMT), while inducing apoptosis. In this chapter, we summarized these findings which were based on the in-vitro applications of five specific atypical PKC (aPKC) inhibitors. In addition, the underlying mechanisms of the transcriptional regulation of PRKCI gene expression in melanoma is also discussed. Results demonstrated that c-Jun promotes PRKCI expression along with Interleukin (IL)-6/8. Furthermore, forkhead box protein O1 (FOXO1) acts as a downregulator of PRKCI expression upon stimulation of IL-17E and intercellular adhesion molecule 1 (ICAM-1) in melanoma cells. Overall, the chapter summarizes the importance of PKC-ι/ζ in the progression of melanoma and discusses the cellular signaling pathways that are altered upon inhibitor applications. Finally, we established that aPKCs are effective novel biomarkers for use in the design of novel targeted therapeutics for melanoma

Use of PKC-iota inhibitors for the treatment of glioma

The present invention pertains to use of PKC-iota inhibitors for treatment of glioma. In a specific embodiment, the treatment method comprises administering ICA-1 or a salt thereof to a subject with glioma. In another embodiment, the treatment method comprises contacting glioma cells with an effective amount of ICA-1 or a salt thereof

Detection of PKC-iota as a biomarker for brain tumorigenesis

A method of detecting brain tumorigenesis in a subject, the method including the steps of (a) obtaining a sample from the brain of the human subject, (b) detecting quantitatively or semi-quantitatively in the sample a level of expression for PKC-iota and (c) comparing the expression level in (b) to a level of expression in a normal control, wherein overexpression of PKC-iota, with respect to the control, indicates the presence of a glioma or meningioma in the subject. The present invention is based upon the discovery that PKC-iota levels are elevated during brain tumorigenesis. Furthermore, the proliferation rate of the tumor correlates with the level of PKC-iota. The invention also provides methods of treating gliomas and meningiomas by administering to the subject a compound that inhibits the expression of PKC-iota. The compound can be a small interfering RNA (siRNA) molecule

Prostate carcinogenesis predictor

A method of detecting prostate tumorigenesis in a subject, the method including the steps of (a) obtaining a sample from the prostate of the human subject, (b) detecting quantitatively or semi-quantitatively in the sample a level of expression for PKC-ι and (c) comparing the expression level in (b) to a level of expression in a normal control, wherein overexpression of PKC-ι, with respect to the control, indicates the presence of prostate cancer in the subject. The present invention is based upon the discovery that PKC-ι levels are elevated during prostate tumorigenesis. Furthermore, the proliferation rate of the tumor correlates with the level of PKC-ι. The invention also provides methods of treating prostate cancer by administering to the subject a compound that inhibits the expression of PKC-ι. The compound can be a small interfering RNA (siRNA) molecule

Prostate carcinogenesis predictor

A method of detecting prostate tumorigenesis in a subject, the method including the steps of (a) obtaining a sample from the prostate of the human subject, (b) detecting quantitatively or semi-quantitatively in the sample a level of expression for PKC-ι and (c) comparing the expression level in (b) to a level of expression in a normal control, wherein overexpression of PKC-ι, with respect to the control, indicates the presence of prostate cancer in the subject. The present invention is based upon the discovery that PKC-ι levels are elevated during prostate tumorigenesis. Furthermore, the proliferation rate of the tumor correlates with the level of PKC-ι. The invention also provides methods of treating prostate cancer by administering to the subject a compound that inhibits the expression of PKC-ι. The compound can be a small interfering RNA (siRNA) molecule

Prostate carcinogenesis predictor

A method of detecting prostate tumorigenesis in a subject, the method including the steps of (a) obtaining a sample from the prostate of the human subject, (b) detecting quantitatively or semi-quantitatively in the sample a level of expression for PKC-ι and (c) comparing the expression level in (b) to a level of expression in a normal control, wherein overexpression of PKC-ι, with respect to the control, indicates the presence of prostate cancer in the subject. The present invention is based upon the discovery that PKC-ι levels are elevated during prostate tumorigenesis. Furthermore, the proliferation rate of the tumor correlates with the level of PKC-ι. The invention also provides methods of treating prostate cancer by administering to the subject a compound that inhibits the expression of PKC-ι. The compound can be a small interfering RNA (siRNA) molecule

Protein Kinase C-ζ Stimulates Colorectal Cancer Cell Carcinogenesis via PKC-ζ/Rac1/Pak1/β-Catenin Signaling Cascade

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

Use of PKC-iota inhibitors for the treatment of breast cancer

The subject invention pertains to uses of PKC-iota inhibitors for treatment of breast cancer. In one embodiment, the subject invention provides novel uses of 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl]-,[1R-(1.alp- ha., 2.beta., 3.beta., 4.alpha.)] (ICA-1) and related compounds for treatment of breast cancer. The compounds of the subject invention have potent anti-proliferative effects against human breast cancer cells. The compounds of the subject invention also inhibit the phosphorylation of IKK-.alpha./IKK-.beta., induce chromatin condensation, and/or induce DNA fragmentation in cancer cells