Nutlin-3 downregulates p53 phosphorylation on serine392 and induces apoptosis in hepatocellular carcinoma cells
Xinli Shi1, Jingli Liu2, Laifeng Ren3
1Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041; Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, China.
Abstract:
Drug-resistance and imbalance of apoptotic regulation limit chemotherapy clinical application for the human hepatocellular carcinoma (HCC) treatment. The reactivation of p53 is an attractive therapeutic strategy in cancer with disrupted-p53 function. Nutlin-3, a MDM2 antagonist, has antitumor activity in various cancers. The post-translational modifications of p53 are a hot topic, but there are some controversy ideas about the function of phospho-Ser392-p53 protein in cancer cell lines in response to Nutlin-3. Therefore, we investigated the relationship between Nutlin-3 and phospho-Ser392-p53 protein expression levels in SMMC-7721 (wild-type TP53) and HuH-7 cells (mutant TP53). We demonstrated that Nutlin-3 induced apoptosis through down-regulation phospho-Ser392-p53 in two HCC cells. The result suggests that inhibition of p53 phosphorylation on Ser392 presents an alternative for HCC chemotherapy.
Insights
Nutlin-3, a drug targeting MDM2, induces apoptosis in human hepatocellular carcinoma (HCC) cells. This occurs through down-regulating phospho-Ser392-p53, offering a new avenue for HCC chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) presents challenges in chemotherapy due to drug resistance and disrupted apoptotic regulation.
- Reactivating the tumor suppressor p53 is a promising strategy for cancer therapy, particularly in cancers with compromised p53 function.
- MDM2 antagonists like Nutlin-3 show antitumor potential, but the role of p53 post-translational modifications, specifically phospho-Ser392-p53, in response to Nutlin-3 remains debated.
Purpose of the Study:
- To investigate the relationship between Nutlin-3 treatment and phospho-Ser392-p53 protein expression in HCC cell lines with different TP53 statuses.
- To elucidate the role of p53 phosphorylation at Ser392 in Nutlin-3-induced apoptosis in HCC.
Main Methods:
- Utilized SMMC-7721 (wild-type TP53) and HuH-7 (mutant TP53) human hepatocellular carcinoma cell lines.
- Administered Nutlin-3, an MDM2 antagonist, to the HCC cell lines.
- Assessed the expression levels of phospho-Ser392-p53 protein and evaluated Nutlin-3's effect on apoptosis.
Main Results:
- Nutlin-3 treatment led to the down-regulation of phospho-Ser392-p53 in both wild-type and mutant TP53 HCC cell lines.
- The observed down-regulation of phospho-Ser392-p53 correlated with Nutlin-3-induced apoptosis in these HCC cells.
- These findings suggest a specific mechanism by which Nutlin-3 exerts its antitumor effects in HCC.
Conclusions:
- Inhibition of p53 phosphorylation at Ser392 is a key mechanism in Nutlin-3-mediated apoptosis in human hepatocellular carcinoma.
- Targeting p53 phosphorylation on Ser392 represents a potential therapeutic strategy for enhancing the efficacy of chemotherapy in HCC treatment.
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