Copper is a heavy metal that plays an essential role in cellular metabolism and other biological functions. In the presence of inflammation, copper levels increase in tissues and are thought to be beneficial, enhancing the body’s defense against infection. On the other hand, copper is also known to be elevated in cancer cells and has specifically been shown to promote colorectal cancer progression.
Since chronic inflammation is a well-characterized risk factor for cancer, especially colon cancer, Xiaoxia Li, PhD, Department of Inflammation & Immunity, sought to uncover how and why copper becomes elevated in these states to better understand the complex relationship between inflammation and cancer.
Inflammatory molecules mobilize copper transport
Dr. Li began her investigation by focusing on signaling of the pro-inflammatory cytokine interleukin 17 (IL-17), which is expressed during chronic inflammation and is known to promote tumor growth. Expression analyses and live staining of preclinical colon organoids revealed that in the presence of IL-17, expression of a protein called STEAP4 (six transmembrane epithelial antigen of prostate 4) increased.
STEAP4 belongs to a subset of proteins called metallo-reductases, which help copper to traverse the cell membrane. With more STEAP4 readily available, more copper is able to enter the cell and, as a result, intracellular levels of the metal increase. In patient-derived colon cancer organoids, Dr. Li’s team noted that elevated STEAP4 levels—and, therefore, more intracellular copper—was associated with significantly enhanced tumor growth.
Intracellular copper disrupts apoptosis and other helpful defenses against tumor growth
On a more mechanistic level, the researchers showed that this increase in tumor growth may be explained by interactions between copper and a protein called XIAP (X-linked inhibitor of apoptosis) once copper has been transported inside of cancer cells.
They found intracellular copper enhanced in a dose-dependent manner the activity of XIAP, which inhibits apoptosis. With higher levels of intracellular copper and reduced rates of cancer cell death, malignant cells were free to proliferate. Additionally, Dr. Li and her team demonstrated that intracellular copper activates a specific region of the XIAP protein that has enzymatic properties, setting off a cascade of signaling events that dysregulates multiple important cell processes, including gene expression and degradation of a protein that leads to cell death.
This study importantly identifies IL-17/STEAP4/XIAP signaling as a potential connection between inflammation, copper and colorectal cancer progression. Previous research from others in the field has shown that copper chelation (a therapeutic approach that removes heavy metals from the body) has had positive results in patients with late-stage, triple-negative breast cancer. While Dr. Li reports that some of the pro-cancer signaling pathways elucidated in this study were interrupted by chelation, more research is necessary.
Yun Liao, PhD, postdoctoral fellow, and Junjie Zhao, PhD, research associate, both members of the Li laboratory, were co-first authors on the study, which was published in Nature Communications and supported by the National Cancer Institute and the National Heart, Lung and Blood Institute, parts of the National Institutes of Health. Dr. Li holds the Paul L. Fox, PhD, Endowed Chair in Molecular Medicine.
Image: Immunostaining for STEAP4 expression in human normal colon and tumor colon tissues