Function And Regulatory Mechanism Of Mutant P53 In Cancer Therapy

The occurrence and development of cancer is a major problem that humans need to overcome.We mainly take colorectal cancer as the research object.It shows that the colon cancer gradually have high incidence and mortality rates according to the survey data.In addition to,p53 gene is frequently mutated.It was found that patients with colon cancer mostly showed drug tolerance in the course of clinical treatment.In addition,the molecular regulatory mechanism of mutant p53 is not yet clear.It is well known that p53 wild type could regulate the expression of Puma and induce apoptosis.The research of our group shows that wild-type p53 could upregulate the expression of its direct downstream targets PUMA,p21 under the chemotherapy drug of 5Fu.In contrast,mutant p53 cannot up-regulate the expression of PUMA and p21 due to the expression of PUMA transcription.Furthermore,mutant p53 could not bind to the promoter of PUMA,which inhibits the transcription level of PUMA,making cancer patients exhibit drug resistance and have no effect therapeutic.Mutant p53 could not bind to the promoter of PUMA to activate its transcription like WT p53 did,while overexpressed WT p53 could significantly increased the expression of PUMA and rescued PUMA-induced subsequent apoptosis.Mutant p53 shows the loss of the tumor suppressor function of wild-type p53.In order to further study and discuss the basic mechanism of mutant p53 inhibit the occurrence of apoptosis and understand its important role in tumorigenesis and development,we need to dig deeper into the hidden mechanism behind it to alleviate the pain of cancer patients.Further studies showed that p53 could be used as a transcription factor to initiate the transcription of PHLPPL.The expression level of PHLPPL was lower in p53 mutant compared with p53 wild-type cells,which showed the inhibition of PHLPPL transcription.According to the relevant experimental results,we found that the mutant p53 down-regulates its expression level by inhibiting the transcription of PHLPPL and regulates downstream molecules.The results show that the activity of Akt could be directly inhibited by PHLPP,which could dephosphorylate the hydrophobic groups of Akt1 and Akt3.The mutant p53 inhibit the expression of PHLPPL,thereby enhancing the expression of Akt and mTOR.The inhibitor of mTOR could significantly reduce the expression of PD-L1 in mutant p53.P53 mutant rely on the PHLPPL-Akt-mTOR signaling pathway to trigger an increased immune escape of PD-L1.The use of mTOR inhibitors in combination with PD-L1 antibodies combine the molecular mechanisms of biological signaling pathways with immunotherapy,providing an important theoretical basis for the development of drugs for cancer treatment and bringing gospel to cancer patients.