Jung Ji-Won, Cho Sung-Dae, Ahn Nam-Shik, Yang Se-Ran, Park Joon-Suk, Jo Eun-Hye, Hwang Jae-Woong, Aruoma Okezie I, Kang Kyung-Sun, Lee Yong-Soon
Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1767-72. doi: 10.1089/ars.2005.7.1767.
Sodium butyrate (NaBu) has an inhibitory effect on histone deacetylases (HDACs). The mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAP, kinase are known to be modulated during NaBu-induced apoptosis. In the present study, we showed that low concentrations of NaBu could induce apoptosis synergistically with the inhibition of p38 MAP kinase as proven by using specific p38 MAP kinase inhibitor and dominant negative p38 transfection in a ras-transformed rat liver epithelial cell line (WB-ras). There were no changes in HDAC1, suggesting that NaBu might be able to kill transformed cells bypassing the HDAC inhibitory effect. We further demonstrated that inhibition of p38 MAP kinase potentiated apoptotic cascades, including cleavage of poly(ADP-ribose) polymerase, caspase-3, and decrease in Bcl-2/Bax ratio even at a lower concentration of NaBu. Thus, p38 MAP kinase played inhibitory roles in NaBu-induced apoptosis, and simultaneous modulation of MAP kinases in NaBu treatment could increase the efficiency of the chemotherapeutic effect of NaBu.
丁酸钠（NaBu）对组蛋白脱乙酰酶（HDACs）具有抑制作用。有丝分裂原活化蛋白（MAP）激酶，如细胞外信号调节激酶1/2（ERK1/2）和p38 MAP激酶，已知在NaBu诱导的细胞凋亡过程中受到调节。在本研究中，我们发现低浓度的NaBu可与p38 MAP激酶的抑制协同诱导细胞凋亡，这一点通过在ras转化的大鼠肝上皮细胞系（WB-ras）中使用特异性p38 MAP激酶抑制剂和显性负性p38转染得以证实。HDAC1没有变化，这表明NaBu可能能够绕过HDAC抑制作用杀死转化细胞。我们进一步证明，即使在较低浓度的NaBu下，抑制p38 MAP激酶也能增强凋亡级联反应，包括多聚（ADP-核糖）聚合酶、半胱天冬酶-3的裂解以及Bcl-2/Bax比值的降低。因此，p38 MAP激酶在NaBu诱导的细胞凋亡中起抑制作用，并且在NaBu处理过程中同时调节MAP激酶可以提高NaBu化疗效果的效率。
