Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma

CutaneousT-celllymphoma(CTCL) is an aggressiveneoplasmwith 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 inCTCLhave not beenpreviously investigated. Present studies demonstrate thatMUC1-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, inducedROS-mediated late apoptosis/necrosis. TargetingMUC1-CinCTCLtumor xenograft models demonstrated significant decreases in disease burden. These findings indicate thatMUC1-Cmaintains redox balance inCTCLcells and is thereby a novel target for the treatment of patients with CTCL.