Chemistry and Chemical Biology ETDs

Publication Date

Spring 4-7-2022

Abstract

Iron is essential part of the human metabolism. It is a catalytic co-factor for many proteins, but it generates harmful reactive oxygen species in human body. Also, many irons metabolic genes are changes in human cancer cells compared to normal cells, leading to iron accumulation in cancer cells especially in colorectal cancer.

Due to iron’s significant role in colorectal cancer promotion, much research is focused on its role in colorectal cancer genesis. But some important metabolic aspects are not fully addressed and researched. One key aspect of iron on colorectal cancer cell progression is hemin iron. Much research warned hemin iron role in colorectal cancer cell promotion, but nobody addressed sestirn2 and hemin iron relationship on tumor progression. Sestrin2 is already known to be highly expressed colorectal tumor and neutralize excess reactive oxygen species in colorectal cancer cells. We found sestrin2 is overexpressed in colorectal cancer cells and promotes colorectal cancer development under hemin iron conditions through generating adequate reactive oxygen species. Next, we are looking for another protein TFRC for iron uptake. TFRC is membrane receptor protein which helps iron influx in the cell. TFRC is highly upregulated in colorectal cancer cells, but its exact mechanism on tumor progression is not fully addressed. We found TFRC disruption or iron restriction deactivates the TNKS activity, which drives beta-catenin signaling and colon tumorigenesis. Importantly, we discovered that the combination of iron chelators and DNA damage agents has a synergistic effect in killing human colorectal cancer cells, which provides a new therapeutic approach. To address TFRC high expression in human colorectal cancer cells, we are looking for pathways, which affects TFRC high expression in human. TFRC is affected by Iron-responsive element-binding protein 2 (IRP2) which expression is also maintained by cellular iron status such as ferritin heavy chains. To do so, we are focusing on the role of NCOA4-mediated ferritinophagy on colon tumorigenesis. NCOA4 is an autophagy receptor of for the iron storage protein ferritin. We found NCOA4 knockout surprisingly caused cellullar and mitochondrial iron accumulation in colorectal cancer cells through Iron-responsive element-binding protein 2 (IRP2) and TFRC upregulation, which promoted mitochondrial reactive oxygen species production and colorectal tumor growth. From these novel findings, we can develop better strategies to target iron metabolism for colorectal cancer therapy in the future.

Language

English

Keywords

Iron, Colorectal cancer, TFRC, Sestrin2 and NCOA4

Document Type

Dissertation

Degree Name

Chemistry and Chemical Biology

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Jeremy adwards

Second Committee Member

Changjian Feng

Third Committee Member

Mark Walker

Fourth Committee Member

Xiang Xue

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