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

Abstract

• MUC1-C oncoprotein contributes toward maintenance of redox balance in CTCL.• Targeting the MUC1-C oncoprotein in CTCL cells induces ROS-mediated death highlighting its potential as an effective strategy.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. (Blood. 2015;126(3):354-362)

Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma

“…All cell lines were grown as previously described (ref. 7). All cell lines were tested for mycoplasma detection with the MycoSEQ TM Mycoplasma Detection Assay from Applied Biosystems prior to use.…”

“…We recently demonstrated that MUC1-C is overexpressed in CTCL cells (ref. 7). We have developed a clinical grade cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for nuclear translocation and downstream signaling (ref 8.…”

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

“…It is overexpressed on CTCL cell lines as well as primary CTCL cells in contrast to T cells of healthy individuals and malignant B cells. A newly developed inhibitor of mucin 1 (GO-203) caused accumulation of ROS, late apoptosis, and necrosis, leading to cell death [81]. A phase II study in relapsed, refractory, or unfit acute myeloid leukemia patients is currently recruiting (NCT02204085).…”

Innovative Behandlungskonzepte mit Modulation der Mikroumgebung beim kutanen T-Zell-Lymphom

“…Im Vergleich zu gesunden T-Zellen und malignen B-Zellen wird es auf CTCL-Zelllinien sowie primären CTCL-Zellen überexprimiert. Ein neu entwickelter Mucin-1-Inhibitor (GO-203) bewirkte die Akkumulation von ROS, späte Apoptose und Nekrose und somit den Zelltod [81]. Für eine Phase-II-Studie mit Patienten mit rezidivierender, refraktärer oder für andere Therapien ungeeigneter akuter myeloischer Leukämie werden derzeit Teilnehmer rekrutiert (NCT02204085).…”