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.2015 May 1;460(2):375-9.
doi: 10.1016/j.bbrc.2015.03.041. Epub 2015 Mar 16.

Anticancer drug bortezomib increases interleukin-8 expression in human monocytes

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Anticancer drug bortezomib increases interleukin-8 expression in human monocytes

Shannon Sanacora et al. Biochem Biophys Res Commun..

Abstract

Bortezomib (BZ) is the first clinically approved proteasome inhibitor that has shown remarkable anticancer activity in patients with hematological malignancies. However, many patients relapse and develop resistance; yet, the molecular mechanisms of BZ resistance are not fully understood. We have recently shown that in solid tumors, BZ unexpectedly increases expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8), while it inhibits expression of other NFκB-regulated genes. Since monocytes and macrophages are major producers of IL-8, the goal of this study was to test the hypothesis that BZ increases the IL-8 expression in human monocytes and macrophages. Here, we show that BZ dramatically increases the IL-8 expression in lipopolysaccharide (LPS)-stimulated U937 macrophages as well as in unstimulated U937 monocytes and peripheral blood mononuclear cells, while it inhibits expression of IL-6, IL-1 and tumor necrosis factor-α. In addition, our results show that the underlying mechanisms involve p38 mitogen-activated protein kinase, which is required for the BZ-induced IL-8 expression. Together, these data suggest that the BZ-increased IL-8 expression in monocytes and macrophages may represent one of the mechanisms responsible for the BZ resistance and indicate that targeting the p38-mediated IL-8 expression could enhance the BZ effectiveness in cancer treatment.

Keywords: Bortezomib; Interleukin-8; Macrophages; Monocytes; NFκB; p38 MAPK.

Copyright © 2015 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Conflict of Interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Bortezomib specifically induces IL-8 mRNA expression in LPS-stimulated U937 macrophages
U937 cells were differentiated with 10 ng/ml PMA for 24 hours, and stimulated with LPS (1 μg/ml) in the absence or presence of 100 nM BZ. mRNA levels were measured by quantitative RT-PCR using β-actin as a control. The values represent the mean +/− SE of four experiments. Asterisks denote a statistically significant (p<0.05) change compared to LPS alone.
Figure 2
Figure 2. Bortezomib specifically induces IL-8 release from LPS-stimulated U937 macrophages
U937 cells were differentiated with 10 ng/ml PMA for 24 hours, and stimulated with LPS (1 μg/ml) in the absence or presence of 100 nM BZ. Cytokine release was measured in cell culture supernatants by ELISA. The values represent the mean +/− SE of four experiments. Asterisks denote a statistically significant (p<0.05) change compared to LPS alone.
Figure 3
Figure 3. BZ increases p38 nuclear accumulation in LPS-stimulated U937 macrophages
Western blotting of cytoplasmic (CE) and nuclear extracts (NE) prepared from U937 cells differentiated with 10 ng/ml PMA for 24 hours, and stimulated with LPS (1 μg/ml) in the absence or presence of 100 nM BZ. The western blots were analyzed by using IKKα, IKKβ, and p38 MAPK specific antibodies. The presence of cytoplasmic proteins in nuclear fraction was evaluated by re-probing the membrane with lactate dehydrogenase (LDH) antibody. Nuclear contamination in the cytoplasmic fraction was assessed by using lamin B specific antibody. To confirm equal protein loading, the membrane was stripped and re-probed with actin antibody.
Figure 4
Figure 4. The BZ-increased IL-8 in human monocytes is mediated by p38 MAPK
(A) Real time RT-PCR analysis of IL-8 mRNA levels in U937 cells pre-treated 2 hours with p38 inhibitor SB203580 (10 μM) or IKK inhibitor PS1145 (20 μM), before 6-hour incubation with 100 nM BZ. The values represent the mean +/− SE of three experiments; the asterisk denotes a statistically significant (p<0.05) inhibition compared to cells treated with BZ only.(B) Real time RT-PCR analysis of IL-8 mRNA levels in U937 cells transfected with control, p38, IKKα, or IKK siRNA and then incubated 6 hours with 100 nM BZ. The values represent the mean +/− SE of three experiments; the asterisk denotes a statistically significant (p<0.05) inhibition compared to cells transfected with control siRNA.(C) Cytokine release measured by ELISA in cell culture supernatants of PBMC (1×106/ml) incubated 24 hours with 100 nM BZ. The values represent the mean +/− SE of three experiments. The asterisk denotes a statistically significant (p<0.05) change compared to untreated (UT) cells.
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