Butyrate regulates the expression of inflammatory and chemotactic cytokines in human acute leukemic cells during apoptosis

• Published in: Cytokine (Philadelphia, Pa.) Vol. 84; pp. 74 - 87
• Main Authors: Pulliam, Stephanie R., Pellom, Samuel T., Shanker, Anil, Adunyah, Samuel E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2016
• Subjects: Acute myeloid leukemia; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Butyrate; Butyrates - pharmacology; Caspase 3 - metabolism; Cell Line; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Chemokine CCL5 - metabolism; Chemokines - metabolism; Cytokines; Gene Expression - drug effects; HL-60 Cells; Humans; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Leukemia - drug therapy; Leukemia - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Migration; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Tumor Microenvironment - drug effects; U937 Cells; Valproic Acid - pharmacology; Inflammation; Cytokines; Acute myeloid leukemia; Migration; Butyrate
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2016.05.014

•During apoptosis, butyrate differentially regulates inflammatory cytokines.•Butyrate suppresses CCL2, CCL5, and subsequently monocyte migration.•Expression of CCL5 may be partially dependent on p38 MAPK.•Induction of CCL2 expression may be dependent on activation of AKT and ERK.•The regulation of cytokines is dependent on stage of maturation in leukemia. Butyrate is a histone deacetylase inhibitor implicated in many studies as a potential therapy for various forms of cancer. High concentrations of butyrate (>1.5mM) 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-à-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 24h, 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-AKT 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.