P53 is a critical tumor suppressor gene, activating p53 and its downstream targets to induce apoptosis is a promising way for cancer therapy. However, more than 50% of cancer patients have p53 mutations, which may cause cancer therapy resistance, and the underline mechanism is poorly understood. Here, we found that cell viability decrease and apoptosis induced by p53-dependent traditional drugs in colon cancer cells were eliminated in p53 mutant cells. Mutant p53 did not up-regulate the expression of its direct downstream targets PUMA and p21, due to the inhibition of PUMA transcription. Furthermore, mutant p53 could not bind to the promoter of PUMA to activate its transcription like WT p53 did, while overexpressed WT p53 rescued PUMA-induced subsequent apoptosis. In conclusion, our findings demonstrate mutant p53 may cause chemo-resistance of tumor because of inactivating PUMA transcription, which prompts some new insights for clinical therapy of cancer patients with mutant p53.
In recent years, many studies have shown that autophagy plays a vital role in the resistance of tumor chemotherapy. However, the interaction between autophagy and cell death has not yet been clarified. In this study, a new specific ERK inhibitor CC90003 was found to suppress colorectal cancer growth by inducing cell death both in vitro and in vivo. Studies have confirmed that higher concentrations of ROS leads to autophagy or cell death. In this research, the role of CC90003-induced ROS was verified. But after inhibiting ROS by two kinds of ROS inhibitors NAC and SFN, the autophagy induced by CC90003 decreased, while cell death strengthened. In parallel, protective autophagy was also induced, while in a p53-dependent manner. After silencing p53 or using the p53 inhibitor PFTα, the autophagy induced by CC90003 was weakened and the rate of cell death increases. Therefore, we confirmed that CC90003 could induce autophagy by activating ROS/p53. Furthermore, in the xenograft mouse model, the effect was obtained remarkably in the combinational treatment group of CC90003 plus CQ, comparing with that of the single treatment groups. In a word, our results demonstrated that targeting ERK leads to cell death and p53/ROS-dependent protective autophagy simultaneously in colorectal cancer, which offers new potential targets for clinical therapy.
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