Mutant p53 drives cancer chemotherapy resistance due to loss of function on activating transcription of PUMA
Mutant p53 drives cancer chemotherapy resistance due to loss of function on activating transcription of PUMA
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p53 突变体因 PUMA 转录激活功能丧失而导致癌症化疗耐药
DOI：
10.1080/15384101.2019.1688951
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发表时间：
2019-11-16
期刊：
影响因子：
4.3
通讯作者：
Zhang, Yingjie
中科院分区：
文献类型：
--
作者：
Huang, Yuan;Liu, Nannan;Zhang, Yingjie
摘要P53是一种重要的抑癌基因，激活p53及其下游靶点诱导细胞凋亡是肿瘤治疗的一个重要途径。然而，超过50%的癌症患者具有p53突变，这可能导致癌症治疗抗性，并且对潜在机制知之甚少。在这里，我们发现，p53依赖性的传统药物在结肠癌细胞中诱导的细胞活力下降和凋亡在p53突变细胞中被消除。突变型p53不上调其直接下游靶点p53 A和p21的表达，这是由于p53 A转录的抑制。此外，突变型p53不能像野生型p53那样与PUMA的启动子结合以激活其转录，而过表达的野生型p53挽救了PUMA诱导的随后的凋亡。结论：突变型p53可能通过抑制p53基因的转录而导致肿瘤的化疗耐药，这为突变型p53的临床治疗提供了新的思路。缩略语：儿童权利委员会：结直肠癌; CDK：细胞周期蛋白依赖性激酶; A：p53上调凋亡调节因子; PDGF：血小板衍生生长因子; WT p53：野生型p53蛋白; mutp 53：突变型p53蛋白; BAX：Bcl-2相关X蛋白; NOXA：佛波醇-12-肉豆蔻酸-13-乙酸诱导蛋白1。
ABSTRACT 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. Abbreviations: CRC: Colorectal cancer; CDKs: Cyclin-dependent kinases; PUMA: p53 up-regulated modulator of apoptosis; PDGF: the platelet-derived growth factor; WT p53: wild-type p53 protein; mutp53: mutant p53 proteins; BAX: Bcl-2-associated X protein; NOXA: Phorbol-12-myristate-13-acetate-induced protein 1.