Interferon-stimulated gene 15 (ISG15) is an ubiquitin-like protein that becomes conjugated to many cellular proteins upon activation by interferon-alpha. The pathway incorporating ISG15 activity is highly elevated in breast cancer, but how the ISG15 pathway contributes to breast tumorigenesis had not been studied to any great extent.
In the current study, using the gene disruption approach (gene knock-down), investigators at the Louisiana State University School of Medicine (New Orleans, USA) demonstrated that both ISG15 and UbcH8 (ISG15-specific conjugating enzyme) disrupted F-actin architecture and formation of focal adhesions in ZR-75-1 breast cancer cells. In addition, ISG15 and UbcH8 promoted breast cancer-cell migration. They also demonstrated that ISG15 inhibited ubiquitin/26S proteasome-mediated turnover of proteins implicated in tumor cell motility, invasion, and metastasis.
The results, which were published in the January 2012 issue of the journal Experimental Biology and Medicine, suggest that the aberrant activation of the ISG15 pathway confers a motile phenotype to breast cancer cells by disrupting cell architecture and stabilizing proteins involved in cell motility, invasion, and metastasis.
First author Dr. Shyamal Desai, assistant professor of biochemistry and molecular biology at the Louisiana State University School of Medicine, said, “Using ISG15 and UbcH8 gene knocked-down approach, our recent published and unpublished results explicitly demonstrated that the ISG15 pathway inhibits the ubiquitin-mediated proteasome-dependent protein degradation in breast cancer cells. We were the first to recognize this antagonizing effect of ISG15 in cancer cells.”
“Disruption of cellular architecture is a hallmark of cancer,” said Dr. Desai. “The ISG15 pathway is also elevated in a variety of tumors. Our results therefore reveal that the ISG15 pathway, which is aberrantly elevated in tumors could disrupt cell architecture and contribute to breast cancer cell motility. Because the cellular architecture is conserved and the ISG15 pathway is constitutively activated in tumor cells of different lineages, our observations in breast cancer must hold true for many other tumors.”
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