Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Mildred Acevedo-Duncan, Ph.D.

Committee Member

Abdul Malik, Ph.D.

Committee Member

Wayne Guida, Ph.D.

Committee Member

Meera Nanjundan, Ph.D.

Keywords

CRC, ICA-I, Protein Kinase, PKC-ζ, PKC-ι, ζ-Stat

Abstract

Colorectal cancer (CRC) is the third most common malignancy and the fourth most common cause of cancer-related death worldwide. CRC is a 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 are still a significant challenge. Moreover, the treatment of metastatic CRC considered palliative for many years aimed for an improved life, with little hope of a cure, highlighting the need for developing novel targeted therapy for CRC. Hence, investigating new molecular mechanism(s) that lead to colorectal carcinogenesis may give insight into the therapeutic target. Human protein kinases constitute a complicated system with complex internal and external interactions, which stimulates various cellular processes such as cell growth, metabolism, survival, and apoptosis. In this study, the role of atypical Protein Kinase C (aPKC) on CRC was investigated by using two inhibitors: 1) ICA-I, an inhibitor of PKC-ι, and 2) ζ-Stat, an inhibitor of PKC-ζ. The cell lines tested were CCD18CO normal colorectal; and LoVo and RKO metastatic CRC cells. Our findings suggest that the aPKCs are responsible for the abnormal growth, proliferation, and metastasis of metastatic CRC cells via aPKC/Rac1/Pak1/β-Catenin pathway and aPKC/Slingshot/cofilin pathways. Moreover, the combination of aPKC inhibitors works synergistically with the clinically available drug such as 5-Fluorouracil (5-FU) to retard the proliferation and induce massive apoptosis in CRC cells. However, the inhibition of aPKCs did not bring any significant toxicity on CCD18CO healthy cells. These results suggest the possibility of utilizing PKC-ζ inhibitor to block CRC cell growth, proliferation, and metastasis.

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