Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
Curr Pharm Des. 2011;17(6):610-7. doi: 10.2174/138161211795222658.
Since p53 is the strongest tumor suppressor gene, which can regulate apoptosis, cell cycle arrest and senescence, re-activation of p53 and its pathway seem to be very plausible target for cancer therapy. However, in 50% of human cancers, p53 itself is mutated. In addition, in remaining half of cancers, it is inactivated by distortion of signaling pathways. Moreover, differentially from typical tumor suppressor genes such as Rb, p53 mutations in its DNA binding domain show the dominant negative effect on p53 function. Here, we describe the novel p53 inactivation mechanism by oncogenic K-Ras-Snail axis and smart strategy to reactivation of p53 suppressed by oncogenic K-Ras-Snail through small chemicals (GN25, 29). Since K-Ras mutation is frequently occurred in human pancreatic, colon, and lung cancer, we discuss the clinical implication of new small Snail-p53 inhibitor on these cancers. In addition, we suggest possibility of reactivation of wild type p53, governed by mutant p53, is suggested using our chemicals. Through this, we will provide the new strategy to handling the K-Ras mutated human cancers including pancreatic, lung and colon cancers.
由于 p53 是最强的肿瘤抑制基因，能够调节细胞凋亡、细胞周期停滞和衰老，因此重新激活 p53 及其通路似乎是癌症治疗的非常合理的靶点。然而，在 50%的人类癌症中，p53 本身发生了突变。此外，在剩下的一半癌症中，其信号通路的失活导致 p53 失活。此外，与典型的肿瘤抑制基因如 Rb 不同，p53 在其 DNA 结合域的突变表现出对 p53 功能的显性负效应。在这里，我们描述了癌基因 K-Ras-Snail 轴导致 p53 失活的新机制，以及通过小分子 (GN25、29) 重新激活被癌基因 K-Ras-Snail 抑制的 p53 的智能策略。由于 K-Ras 突变在人类胰腺、结肠和肺癌中经常发生，我们讨论了新型小 Snail-p53 抑制剂对这些癌症的临床意义。此外，我们还提出了使用我们的化学物质重新激活受突变 p53 调控的野生型 p53 的可能性。通过这种方式，我们将为处理包括胰腺、肺和结肠在内的携带 K-Ras 突变的人类癌症提供新的策略。
