Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Cellular and Molecular Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
J Cell Biochem. 2019 Jun;120(6):9125-9137. doi: 10.1002/jcb.28188. Epub 2019 Jan 4.
Fragile histidine trail (FHIT) is a tumor suppressor in response to DNA damage which has been deleted in various tumors. However, the signaling mechanisms and interactions of FHIT with regard to apoptotic proteins including p53 and p38 in the DNA damage-induced apoptosis are not well described. In the present study, we used etoposide-induced DNA damage in MCF-7 as a model to address these crosstalks. The time course study showed that the expression of FHIT, p53, and p38MAPK started after 1 hour following etoposide treatment. FHIT overexpression led to increase p53 expression, p38 activation, and augmented apoptosis following etoposide-induced DNA damage compared to wild-type cells. However, FHIT knockdown blocked p53 expression, delayed p38 activation, and completely inhibited etoposide-induced apoptosis. Inhibition of p38 activity prevented induction of p53, FHIT, and apoptosis in this model. Thus, activation of p38 upon etoposide treatment leads to increase in FHIT and p53 expression. In p53 knockdown MCF-7, the FHIT induction was hampered but p38 activation was induced in lower doses of etoposide. In p53 knockdown cells, inhibition of p38 induced FHIT expression and apoptosis. Our data demonstrated that the exposure of MCF-7 cells to etoposide increases apoptosis through a mechanism involving the activation of the p38-FHIT-p53 pathway. Moreover, our findings suggest signaling interaction for these pathways may represent a promising therapy for breast cancer.
脆性组氨酸三联体（FHIT）是一种对 DNA 损伤有反应的肿瘤抑制因子，它在各种肿瘤中都被删除了。然而，FHIT 与包括 p53 和 p38 在内的凋亡蛋白在 DNA 损伤诱导的凋亡中的信号机制和相互作用尚未得到很好的描述。在本研究中，我们使用依托泊苷诱导的 MCF-7 中的 DNA 损伤作为模型来解决这些串扰问题。时程研究表明，在依托泊苷处理后 1 小时，FHIT、p53 和 p38MAPK 的表达开始。与野生型细胞相比，FHIT 过表达导致依托泊苷诱导的 DNA 损伤后 p53 表达增加、p38 激活和凋亡增加。然而，FHIT 敲低阻断了 p53 表达，延迟了 p38 激活，并完全抑制了依托泊苷诱导的凋亡。在该模型中，p38 活性的抑制阻止了 p53、FHIT 和凋亡的诱导。因此，依托泊苷处理后 p38 的激活导致 FHIT 和 p53 表达增加。在 p53 敲低的 MCF-7 中，FHIT 的诱导受到阻碍，但在较低剂量的依托泊苷中 p38 的激活被诱导。在 p53 敲低的细胞中，p38 的抑制诱导 FHIT 表达和凋亡。我们的数据表明，MCF-7 细胞暴露于依托泊苷会通过一种涉及 p38-FHIT-p53 途径激活的机制增加细胞凋亡。此外，我们的发现表明这些途径的信号相互作用可能代表治疗乳腺癌的一种有前途的方法。
