title: Bortezomib inhibits expression of TGF-β1, IL-10, and CXCR4, resulting in decreased survival and migration of cutaneous T cell lymphoma cells.
abstract: Increased expression of the immunosuppressive cytokines, TGF-β1 and IL-10, is a hallmark of the advanced stages of cutaneous T cell lymphoma (CTCL), where it has been associated with suppressed immunity, increased susceptibility to infections, and diminished antitumor responses. Yet, little is known about the transcriptional regulation of TGF-β1 and IL-10 in CTCL, and about their function in regulating the CTCL cell responses. In this article, we show that TGF-β1 and IL-10 expression in CTCL cells is regulated by NF-κB and suppressed by bortezomib (BZ), which has shown promising results in the treatment of CTCL. However, although the TGF-β1 expression is IκBα dependent and is regulated by the canonical pathway, the IL-10 expression is IκBα independent, and its inhibition by BZ is associated with increased promoter recruitment of p52 that characterizes the noncanonical pathway. TGF-β1 suppression decreases CTCL cell viability and increases apoptosis, and adding exogenous TGF-β1 increases viability of BZ-treated CTCL cells, indicating TGF-β1 prosurvival function in CTCL cells. In addition, TGF-β1 suppression increases expression of the proinflammatory cytokines IL-8 and IL-17 in CTCL cells, suggesting that TGF-β1 also regulates the IL-8 and IL-17 expression. Importantly, our results demonstrate that BZ inhibits expression of the chemokine receptor CXCR4 in CTCL cells, resulting in their decreased migration, and that the CTCL cell migration is mediated by TGF-β1. These findings provide the first insights into the BZ-regulated TGF-β1 and IL-10 expression in CTCL cells, and indicate that TGF-β1 has a key role in regulating CTCL survival, inflammatory gene expression, and migration.
authors: Department of Biological Sciences, St. John's University, New York, NY 11439; and.
authors: Tzu-Pei
authors: TP
authors: Chang
authors: Department of Pharmaceutical Sciences, St. John's University, New York, NY 11439.
authors: Vladimir
authors: V
authors: Poltoratsky
authors: Department of Biological Sciences, St. John's University, New York, NY 11439; and vancuroi@stjohns.edu.
authors: Ivana
authors: I
authors: Vancurova
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines / Q000494:pharmacology*; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C527276:CXCR4 protein, human; D020672:I-kappa B Proteins; D020381:Interleukin-17; D016209:Interleukin-8; D016328:NF-kappa B; D011719:Pyrazines; D019718:Receptors, CXCR4; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex