1] The Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan 646000, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China [3] Department of Hepatobiliary Surgery of the Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan, China.
Cell Death Dis. 2013 Oct 24;4(10):e883. doi: 10.1038/cddis.2013.419.
Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to induce apoptosis in some types of cells. However, the underlying mechanisms remain largely unclear. Using a DNA microarray analysis, we found that the expression of many genes was downregulated upon treatment with compound C. Importantly, compound C caused transcriptional repression with the induction of p53, a well-known marker of transcriptional stress response, in several cancer cell lines. Compound C did not induce the phosphorylation of p53 but dramatically increased the protein level of p53 similar to some other transcriptional inhibitors, including 5,6-dichloro-1-β-D-ribobenzimidazole (DRB). Consistent with previous reports, we found that compound C initiated apoptotic death of cancer cells in an AMPK-independent manner. Similar to DRB and actinomycin D (ActD), two classic transcription inhibitors, compound C not only resulted in the loss of Bcl-2 and Bcl-xl protein but also induced the phosphorylation of eukaryotic initiation factor-alpha (eIF2α) on Ser51. Hence, the phosphorylation of eIF2α might be a novel marker of transcriptional inhibition. It is noteworthy that compound C-mediated apoptosis of cancer cells is correlated with decreased expression of Bcl-2 and Bcl-xl and the phosphorylation of eIF2α on Ser51. Remarkably, compound C exhibits potent anticancer activities in vivo. Taken together, our data suggest that compound C may be an attractive candidate for anticancer drug development.
化合物 C 是一种众所周知的 AMP 激活的蛋白激酶 (AMPK) 抑制剂，已被报道可诱导某些类型的细胞凋亡。然而，其潜在的机制在很大程度上仍不清楚。通过 DNA 微阵列分析，我们发现化合物 C 处理后许多基因的表达下调。重要的是，化合物 C 引起了转录抑制，同时诱导了 p53 的表达，p53 是转录应激反应的一个众所周知的标志物，在几种癌细胞系中均有发现。化合物 C 没有诱导 p53 的磷酸化，但与其他一些转录抑制剂（如 5,6-二氯-1-β-D-核糖苯并咪唑（DRB））一样，显著增加了 p53 的蛋白水平。与之前的报道一致，我们发现化合物 C 以 AMPK 非依赖性的方式引发了癌细胞的凋亡。与 DRB 和放线菌素 D（ActD）这两种经典的转录抑制剂类似，化合物 C 不仅导致了 Bcl-2 和 Bcl-xl 蛋白的丧失，还诱导了真核起始因子-α（eIF2α）在 Ser51 上的磷酸化。因此，eIF2α 的磷酸化可能是转录抑制的一个新标志物。值得注意的是，化合物 C 介导的癌细胞凋亡与 Bcl-2 和 Bcl-xl 的表达降低以及 eIF2α 在 Ser51 上的磷酸化有关。值得注意的是，化合物 C 在体内具有很强的抗癌活性。综上所述，我们的数据表明，化合物 C 可能是一种有吸引力的抗癌药物开发候选物。
