Abstract 142: Sodium butyrate suppresses production of chemokines in human U937 cells
Authors: Stephanie R. Pulliam, Roland Cooper, Samuel E. Adunyah
Journal: Cancer Research (2014)

Abstract Sodium butyrate (NaB) is a sodium salt of butyric acid. It is a HDAC inhibitor implicated in many studies as a potential therapy for various forms of cancer. Due to its ability to promote total and gamma globin during erythroid differentiation, low concentrations (&amp;lt;1.5 mM) of NaB are considered a potential therapy for hemoglobin disorders including sickle cell diseases, leukemia, and β-thalassemia. Previously, high concentrations of NaB (&amp;gt;1.5 mM) have been shown to activate apoptosis in several cancer cell lines including prostate, endometrial, breast and leukemia. Low concentrations of NaB influence multiple signaling pathways that are known mediators of cytokine production. However, it is not known whether high concentrations alter these pathways having the capacity to modulate cytokine expression in cancer cells and alter the cancer microenvironment, which is the purpose of this study. We exposed U937 leukemia cells to NaB at 5 or 10 mM doses for various time points. The culture media of the cells were harvested and analyzed by Human Multi-Analyte Cytokine ELISArray for levels of chemokines and chemotactic properties via migration assay. As evidence of apoptosis, we monitored cells for caspase-3 activation and cell viability. Our results indicate NaB induces a 2-fold activation of caspase-3 but a decrease in cell viability by 60%. Also, NaB induces a significant decrease in levels of chemokines CCL2 and CCL5 in 24 hours. Moreover, monocyte migration towards culture media from NaB treated cells, decreased in time-dependent manner. To elucidate the signaling mechanism(s) used by NaB (5mM), we investigated whether NaB alters the phospho-protein levels of AKT, ERK1/2, p38 and JNK. We observed an increase in phosphorylation of p38 MAPK, but a decrease in ERK1/2 in response to NaB. Also, there was an initial decrease in p-AKT level within 2 minutes suggesting a decline of Akt activation. However, this was followed by re-activation of AKT by 24 hours post-treatment. Interestingly, NaB did not influence activation of JNK. This data suggests that while promoting apoptosis, NaB has the potential to influence cancer microenvironment by inducing differential expression of cytokines. While the mechanism by which NaB induces differential expression of cytokines remains unknown, potentially, it could occur via the AKT and/or MAPK mediated pathways. These effects may influence the biology of normal and cancer cells thereby altering the status of the patient receiving NaB therapy. *Pulliam is supported by NHLBI T32 Pre-doctoral training grant #2-T32-HL007735-16 to Dr. Adunyah and CTSA award #UL1TR000445 from the National Center for Advancing Translational Sciences. Additionally, Dr. Adunyah is supported by NCI Cancer Partnership U54 grant #5-U54-CA163069-02 and NIMHD MeTRC grant #8-U54-MD007593-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Citation Format: Stephanie R. Pulliam, Roland Cooper, Samuel E. Adunyah. Sodium butyrate suppresses production of chemokines in human U937 cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 142. doi:10.1158/1538-7445.AM2014-142