Chemistry and Chemical Biology ETDs

Publication Date

9-21-2021

Abstract

Cancer is one of the biggest threatens to human health. Many people died because of various types of cancer. Colon cancer is one of the leading causes of new incidence and mortality in the whole world. It is important to understand the mechanism of tumorigenesis and development. Based on the mechanisms, we may develop new therapeutics to improve survival rate. In Chapter 2, we discussed the PINK1 function in suppression colon cancer. We found that PINK1 deficiency can promote colon cancer, and PINK1 overexpression suppressed tumor growth in vivo and in vitro. PINK1 can activate its substrate P53, which activates its downstream targets during mitophay. At the same time, PINK1 is also involved in metabolism, that PINK1 can reduce Acetyl-CoA by inhibiting PDHE1α. Cells treated with acetate can rescue PINK1 suppression role in colon cancer. As PINK1 shows multi-function in various diseases, in Chapter 3 we investigated PINK1’s role in inflammation. Mitochondria DNA can activate the NLPR3 inflammation response, we investigated on PINK1’s function in inflammation, we found that some cytokines involved in immune response significantly changed and we observed that when treated the mice with NLRP3 inhibitor, which has a protection role the wild type group, but not in the PINK1 deficiency group. In this on-going project, the mechanism is still elusive, and we need figure out the reasons and provide a potential method for colon cancer treatment. STEAP4 is a metalloreductase maintaining iron and copper homeostasis. STEAP4 is an important enzyme that has multi-functions in the tissue. Dysfunctions of STEAP4 involve in diseases like cancer, immune disease, inflammation, obesity. It is critical to understand the roles STEAP4 plays in the cell. And understanding the mechanisms is an important step in developing new therapeutics. In Chapter 4, we studied STEAP4, which promotes tumor development. We found that STEA4 deficiency has a protection role in colon cancer development, and in vitro study showed that STEAP4 promoted tumor cell growth by increasing ROS level, which can also trigger cell death when the concentration was further increased. We used two drugs that can induce ROS to treat the cells, and it showed that these two drugs can induce apoptosis in STEAP4 overexpression cell line. These findings may provide a potential treatment for colon cancer.

Project Sponsors

Prof. XIANG XUE

Language

English

Keywords

colon cnacer, PINK1, acetyl-CoA, inflammation, STEAP4, ROS

Document Type

Dissertation

Degree Name

Chemistry

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Prof. Jeremy Edwards

Second Committee Member

Prof. Xiang Xue

Third Committee Member

Prof. Changjian Feng

Fourth Committee Member

Prof. Mark Walker

Download

Included in

Chemistry Commons

Share

COinS