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.
Colon cancer is one of the three common malignant tumors, with a lower survival rate. Ipatasertib, a novel highly selective ATP-competitive pan-Akt inhibitor, shows a strong antitumor effect in a variety of carcinoma, including colon cancer. However, there is a lack of knowledge about the precise underlying mechanism of clinical therapy for colon cancer. We conducted this study to determine that ipatasertib prevented colon cancer growth through PUMA-dependent apoptosis. Ipatasertib led to p53-independent PUMA activation by inhibiting Akt, thereby activating both FoxO3a and NF-κB synchronously that will directly bind to PUMA promoter, up-regulating PUMA transcription and Bax-mediated intrinsic mitochondrial apoptosis. Remarkably, Akt/FoxO3a/PUMA is the major pathway while Akt/NF-κB/PUMA is the secondary pathway of PUMA activation induced by ipatasertib in colon cancer. Knocking out PUMA eliminated ipatasertib-induced apoptosis both in vitro and in vivo (xenografts). Furthermore, PUMA is also indispensable in combinational therapies of ipatasertib with some conventional or novel drugs. Collectively, our study demonstrated that PUMA induction by FoxO3a and NF-κB is a critical step to suppress the growth of colon cancer under the therapy with ipatasertib, which provides some theoretical basis for clinical assessment.
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