期刊
CELL CYCLE
卷 18, 期 24, 页码 3442-3455出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2019.1688951
关键词
Mutant p53; chemotherapy resistance; colon cancer; loss-of-function; PUMA
类别
资金
- National Natural Science Foundation of China [31801140, 31701132]
- Fundamental Research Funds for Central Universities of the Central South University (CN) [531118040098, 14700-502044001]
- Basic Research Program of Shenzhen Municipal Science and Technology Innovation Committee [JCYJ20160530192802733]
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.
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