Journal
CYTOKINE
Volume 84, Issue -, Pages 74-87Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2016.05.014
Keywords
Butyrate; Acute myeloid leukemia; Inflammation; Cytokines; Migration
Funding
- NHLBI [2T32HL007735-20, T32 5T32HL007737]
- NCI [U54 CA091408-06, U54 CA091408, 5P50 CA 090949, SCI CA182843, 2 U54 CA163069-05]
- CTSA award (NCATS) [UL1TR000445]
- NCRR [5 U54 RR026140-03]
- NIMHD [8 U54 MD007593-03, 5 U54 RR026140-07 (NCRR)/8 U54 MD007593-06]
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Butyrate is a histone deacetylase inhibitor implicated in many studies as a potential therapy for various forms of cancer. High concentrations of butyrate (>1.5 mM) have been shown to activate apoptosis in several cancer cell lines including prostate, breast, and leukemia. Butyrate is also known to influence multiple signaling pathways that are mediators of cytokine production. The purpose of this study was to evaluate the impact of high concentrations of butyrate on the cancer microenvironment vis-a-vis apoptosis, cellular migration, and capacity to modulate cytokine expression in cancer cells. The results indicate that high concentrations of butyrate induced a 2-fold activation of caspase-3 and reduced cell viability by 60% in U937 leukemia cells. Within 24 h, butyrate significantly decreased the levels of chemokines CCL2 and CCL5 in HL-60 and U937 cells, and decreased CCL5 in THP-1 leukemia cells. Differential effects were observed in treatments with valproic acid for CCL2 and CCL5 indicating butyrate-specificity. Many of the biological effects examined in this study are linked to activation of the AKT and MAPK signaling pathways; therefore, we investigated whether butyrate alters the levels of phosphorylated forms of these signaling proteins and how it correlated with the expression of chemokines. The results show that butyrate may partially regulate CCL5 production via p38 MAPK. The decrease in p-ERK1/2 and p-ART levels correlated with the decrease in CCL2 production. These data suggest that while promoting apoptosis, butyrate has the potential to influence the cancer microenvironment by inducing differential expression of cytokines. (C) 2016 Elsevier Ltd. All rights reserved.
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