title: Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma.
abstract: 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.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Salvia
authors.initials: S
authors.lastname: Jain
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Dina
authors.initials: D
authors.lastname: Stroopinsky
authors.affiliation: Dana-Farber Cancer Institute, and.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Jacalyn
authors.initials: J
authors.lastname: Rosenblatt
authors.affiliation: Dana-Farber Cancer Institute, and.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Parul
authors.initials: P
authors.lastname: Bhargava
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Clark
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Kristen
authors.initials: K
authors.lastname: Palmer
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Coll
authors.affiliation: Dana-Farber Cancer Institute, and.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Athalia
authors.initials: A
authors.lastname: Pyzer
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Michal
authors.initials: M
authors.lastname: Bar-Natan
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Katarina
authors.initials: K
authors.lastname: Luptakova
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Jon
authors.initials: J
authors.lastname: Arnason
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: Robin
authors.initials: R
authors.lastname: Joyce
authors.affiliation: Dana-Farber Cancer Institute, and.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
authors.affiliation: Beth Israel Deaconess Medical Center.
authors.forename: David
authors.initials: D
authors.lastname: Avigan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018396:Mucin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018396:Mucin-1; D010455:Peptides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009249:NADP; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; D005978:Glutathione