Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, Atlanta, Georgia 30341, USA.
J Cell Biochem. 2012 Jan;113(1):269-81. doi: 10.1002/jcb.23353.
Human lung neoplasms frequently express mutations that down-regulate expression of various tumor suppressor molecules, including mitogen-activated protein kinases such as p38 MAPK. Conversely, activation of p38 MAPK in tumor cells results in cancer cell cycle inhibition or apoptosis initiated by chemotherapeutic agents such as retinoids or cisplatin, and is therefore an attractive approach for experimental anti-tumor therapies. We now report that 4-phenyl-3-butenoic acid (PBA), an experimental compound that reverses the transformed phenotype at non-cytotoxic concentrations, activates p38 MAPK in tumorigenic cells at concentrations and treatment times that correlate with decreased cell growth and increased cell-cell communication. H2009 human lung carcinoma cells and ras-transformed rat liver epithelial cells treated with PBA showed increased activation of p38 MAPK and its downstream effectors which occurred after 4 h and lasted beyond 48 h. Untransformed plasmid control cells showed low activation of p38 MAPK compared to ras-transformed and H2009 carcinoma cells, which correlates with the reduced effect of PBA on untransformed cell growth. The p38 MAPK inhibitor, SB203580, negated PBA's activation of p38 MAPK downstream effectors. PBA also increased cell-cell communication and connexin 43 phosphorylation in ras-transformed cells, which were prevented by SB203580. In addition, PBA decreased activation of JNK, which is upregulated in many cancers. Taken together, these results suggest that PBA exerts its growth regulatory effect in tumorigenic cells by concomitant up-regulation of p38 MAPK activity, altered connexin 43 expression, and down-regulation of JNK activity. PBA may therefore be an effective therapeutic agent in human cancers that exhibit down-regulated p38 MAPK activity and/or activated JNK and altered cell-cell communication.
人类肺部肿瘤经常表达突变，这些突变下调了各种肿瘤抑制分子的表达，包括丝裂原活化蛋白激酶（如 p38MAPK）。相反，肿瘤细胞中 p38MAPK 的激活会导致细胞周期抑制或细胞凋亡，这是实验性抗肿瘤治疗的一种有吸引力的方法。我们现在报告，4-苯基-3-丁烯酸（PBA）是一种实验性化合物，它可以在非细胞毒性浓度下逆转转化表型，在与细胞生长减少和细胞间通讯增加相关的浓度和治疗时间内激活致癌细胞中的 p38MAPK。用 PBA 处理的 H2009 人肺癌细胞和 ras 转化的大鼠肝上皮细胞显示 p38MAPK 及其下游效应物的激活增加，这种激活发生在 4 小时后，并持续超过 48 小时。未转化的质粒对照细胞与 ras 转化和 H2009 癌细胞相比，p38MAPK 的激活较低，这与 PBA 对未转化细胞生长的影响降低有关。p38MAPK 抑制剂 SB203580 消除了 PBA 对 p38MAPK 下游效应物的激活。PBA 还增加了 ras 转化细胞中的细胞间通讯和连接蛋白 43 的磷酸化，这被 SB203580 所阻止。此外，PBA 降低了 JNK 的激活，JNK 在许多癌症中上调。总之，这些结果表明，PBA 通过同时上调 p38MAPK 活性、改变连接蛋白 43 的表达和下调 JNK 活性，对肿瘤细胞发挥其生长调节作用。因此，PBA 可能是一种有效的治疗剂，适用于表现出 p38MAPK 活性下调和/或 JNK 激活和细胞间通讯改变的人类癌症。
