Abstract
Triple negative breast cancer (TNBC) cells express increased levels of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which promotes their proliferation and migration. Because TNBC patients are unresponsive to current targeted therapies, new therapeutic strategies are urgently needed. While proteasome inhibition by bortezomib (BZ) or carfilzomib (CZ) has been effective in treating hematological malignancies, it has been less effective in solid tumors, including TNBC, but the mechanisms are incompletely understood. Here we report that proteasome inhibition significantly increases expression of IL-8, and its receptors CXCR1 and CXCR2, in TNBC cells. Suppression or neutralization of the BZ-induced IL-8 potentiates the BZ cytotoxic and anti-proliferative effect in TNBC cells. The IL-8 expression induced by proteasome inhibition in TNBC cells is mediated by IκB kinase (IKK), increased nuclear accumulation of p65 NFκB, and by IKK-dependent p65 recruitment to IL-8 promoter. Importantly, inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ-treated TNBC cells. These data provide the first evidence demonstrating that proteasome inhibition increases the IL-8 signaling in TNBC cells, and suggesting that IKK inhibitors may increase effectiveness of proteasome inhibitors in treating TNBC.
Highlights
Interleukin-8 (IL-8, CXCL8) is a pro-inflammatory and pro-angiogenic chemokine that stimulates cancer progression by inducing tumor cell proliferation, survival, and migration [1,2]
Since there are no effective therapies for triple negative breast cancer (TNBC), and the effect of proteasome inhibitors (PI) on NFκB-dependent transcription in TNBC cells has never been investigated, in this study, we examined the effect of proteasome inhibition on the expression of NFκB-dependent genes in TNBC cells, and tested the hypothesis that proteasome inhibition induces IL-8 expression, resulting in increased proliferation and migration of TNBC cells
To test the hypothesis that proteasome inhibition increases IL-8 expression in TNBC cells, we first analyzed expression of IL-8, as well as other NFκB-dependent genes, in bortezomib (BZ)treated MDA-MB-231 cells that are characterized by the lack of ER, PR, and Her2 receptors, high proliferation rates and resistance to hormone therapy, and have been widely used as an in vitro model to study TNBC
Summary
Interleukin-8 (IL-8, CXCL8) is a pro-inflammatory and pro-angiogenic chemokine that stimulates cancer progression by inducing tumor cell proliferation, survival, and migration [1,2]. IL8 expression is increased in many types of advanced cancers, including triple negative breast cancer (TNBC), and correlates with poor prognosis [3,4,5,6]. TNBC, characterized by the lack of estrogen (ER), progesterone (PR), and Her receptors, accounts for about 15–20% of all breast cancers, and is the subtype with the worst prognosis. Proteasome inhibition induces IL-8 in triple negative breast cancer cells become drug-resistant, development of novel therapeutic strategies is essential [7]. As single agents, proteasome inhibitors (PI) have failed to show a significant clinical activity in solid tumors, including TNBC [12,13,14,15,16,17], but the responsible mechanisms are not fully understood
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