Journal
BLOOD
Volume 126, Issue 3, Pages 354-362Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-02-628149
Keywords
-
Categories
Funding
- National Institutes of Health National Cancer Institute [P50CA100707, P50CA9368305]
- Conquer Cancer Foundation
- National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR063962, R01AR056720]
- Damon Runyon Clinical Investigator Award
- National Institutes of Health National Institute of Allergy and Infectious Diseases [R01AI097128]
Ask authors/readers for more resources
Cutaneous T-cell lymphoma (CTCL) is an aggressive neoplasm with limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cytotoxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit resistance to ROS-induced apoptosis, the expression and functional significance of MUC1 in CTCL have not been previously investigated. Present studies demonstrate that MUC1-C is overexpressed in CTCL cell lines and primary CTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, induced ROS-mediated late apoptosis/necrosis. Targeting MUC1-C in CTCL tumor xenograft models demonstrated significant decreases in disease burden. These findings indicate that MUC1-C maintains redox balance in CTCL cells and is thereby a novel target for the treatment of patients with CTCL.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available