Bortezomib Inhibits Expression of TGF-β1, IL-10, and CXCR4, Resulting in Decreased Survival and Migration of Cutaneous T Cell Lymphoma Cells

Increased expression of the immunosuppressive cytokines, TGF-beta 1 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-beta 1 and IL-10 in CTCL, and about their function in regulating the CTCL cell responses. In this article, we show that TGF-beta 1 and IL-10 expression in CTCL cells is regulated by NF-kappa B and suppressed by bortezomib (BZ), which has shown promising results in the treatment of CTCL. However, although the TGF-beta 1 expression is I kappa B alpha dependent and is regulated by the canonical pathway, the IL-10 expression is I kappa B alpha independent, and its inhibition by BZ is associated with increased promoter recruitment of p52 that characterizes the noncanonical pathway. TGF-beta 1 suppression decreases CTCL cell viability and increases apoptosis, and adding exogenous TGF-beta 1 increases viability of BZ-treated CTCL cells, indicating TGF-beta 1 prosurvival function in CTCL cells. In addition, TGF-beta 1 suppression increases expression of the proinflammatory cytokines IL-8 and IL-17 in CTCL cells, suggesting that TGF-beta 1 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-beta 1. These findings provide the first insights into the BZ-regulated TGF-beta 1 and IL-10 expression in CTCL cells, and indicate that TGF-beta 1 has a key role in regulating CTCL survival, inflammatory gene expression, and migration.