Sodium butyrate induces senescence and inhibits the invasiveness of glioblastoma cells

Nakagawa,Hidemitsu; Sasagawa,Satoru; Itoh,Kazuyuki

doi:10.3892/ol.2017.7518

Sodium butyrate induces senescence and inhibits the invasiveness of glioblastoma cells

Authors:
- Hidemitsu Nakagawa
- Satoru Sasagawa
- Kazuyuki Itoh
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Affiliations: Department of Neurosurgery, Nozaki Tokushukai Hospital, Daito, Osaka 574‑0074, Japan, Department of Molecular Biology, Research Institute Nozaki Tokushukai, Daito, Osaka 574‑0074, Japan
Published online on: December 5, 2017 https://doi.org/10.3892/ol.2017.7518
Pages: 1495-1502
Copyright: © Nakagawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sodium butyrate (SB), a short chain (C‑4) saturated fatty acid, is present in the human bowel at increased concentrations (~2 mM) as a food metabolite. It has been demonstrated that SB exerts an anti‑tumor effect as a histone deacetylase inhibitor; however, its precise mechanism of action remains to be elucidated. The present study focused on the mechanisms underlying the effects of SB on glioblastoma (GB) cell proliferation, motility and invasion. In human GB A172 cells, flow cytometry and a Boyden chamber assay demonstrated that physiological concentrations of SB (0.25‑4.00 mM) dose‑dependently inhibited cell proliferation and invasion. SB also affected cellular morphology, with increases in cell area and the number of focal adhesions observed. However, the phosphorylation (Y397 site) of focal adhesion kinase (FAK) was increased, while that of myosin light chain (S19 site) was unaltered. All of these SB‑induced effects were reversible and attenuated following SB withdrawal. In addition, A172 cells treated with SB exhibited positivity for senescence‑associated (SA) β‑galactosidase (gal) staining and elevated protein expression of p53 and p21 in a time‑ and dose‑dependent manner, whereas the expression of p21 mRNA decreased. Knockdown of p21 expression using small interfering RNA reversed the inhibition of cell growth inhibition and positivity for SA β‑gal staining, but did not reverse the inhibition of cell motility and enhanced phosphorylation of FAK. This suggests that cells require p21 to induce senescence but not for SB‑mediated decreased motility. Therefore, the current study demonstrated that SB inhibits GB cell proliferation, induces cells to senesce and inhibits tumor cell invasion, indicating that it may be developed as a novel therapeutic strategy to treat GB.

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