title: Butyrate regulates the expression of inflammatory and chemotactic cytokines in human acute leukemic cells during apoptosis.
abstract: 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.
authors.affiliation: School of Graduate Studies and Research, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA; Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Pulliam
authors.affiliation: School of Graduate Studies and Research, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA; Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA; Department of Microbiology and Immunology, School of Medicine, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Pellom
authors.affiliation: School of Graduate Studies and Research, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA; Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA; Host-Tumor Interactions Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Shanker
authors.affiliation: School of Graduate Studies and Research, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA; Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, 1005 Dr. DB Todd, Jr. Blvd., Nashville, TN 37208, USA. Electronic address: sadunyah@mmc.edu.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Adunyah
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D020298:U937 Cells; D014635:Valproic Acid / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002087:Butyrates; D018946:Chemokine CCL5; D018925:Chemokines; D014635:Valproic Acid; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3
keywords: Acute myeloid leukemia; Butyrate; Cytokines; Inflammation; Migration