• Journal of Life Science
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• v.31 no.4
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• pp.400-409
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• 2021

Sanguinarine, a natural benzophenanthridine alkaloid, has been considered a potential therapeutic target for the treatment of cancer because it can induce apoptosis in human cancer cells; however, the underlying mechanisms of action still remain unclear. Tumor suppressor p53 deletion or mutation is an important reason for the resistance of colorectal cancer cells to anticancer agents. Therefore, in the present study, the role of p53 during apoptosis induced by sanguinarine was investigated in p53wild type (WT, p53+/+) and p53null (p53+/+) HCT116 colon carcinoma cells. Sanguinarine significantly caused greater reductions in cell viability in HCT116 (p53+/+) cells than in HCT116 (p53-/-) cells. Consistently, sanguinarine promoted more DNA damage and apoptosis in HCT116 (p53+/+) cells than in HCT116 (p53-/-) cells while increasing the expression of p53 and cyclin-dependent kinase inhibitor p21^WAF1/CIP1. Sanguinarine increased the activity of caspase-8 and caspase-9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and it activated caspase-3, a typical effect caspase, in HCT116 (p53+/+) cells. Sanguinarine also increased the generation of reactive oxygen species (ROS), and the Bax/Bcl-2 ratio, while destroying the integrity of mitochondria in HCT116 (p53+/+) cells, but not in HCT116 (p53-/-) cells. Overall, the results indicate that sanguinarine induced p53-dependent apoptosis through ROS-mediated activation of extrinsic and intrinsic apoptotic pathways in HCT116 colorectal cancer cells.

• Journal of Chest Surgery
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• v.31 no.12
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• pp.1134-1146
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• 1998

Background: The tumor suppressor gene p53 is one of the most frequently altered genes in human tumors, including those of the lung. There is now a compelling evidence that wild-type p53 can negatively influence cell growth by causing G1 arrest or by inducing apoptosis. The possibilities of using p53 for gene therapy are also gathering much interest. Material and Method: Our approach towards understanding p53 function would be to study the biological consequences of overexpression of wild-type p53 in normal and tumor cells by using adenovirus vectors capable of giving high levels of the p53 gene product in cells. We have used this vector containing wild-type p53 to infect tumor cells with different p53 status (null, mutant, or wild-type) to confirm that expression of p53 in null or mutant cell lines becomes possible by Adenovirus-p53 transduction, to examine the effects of high levels of p53 expression on the growth properties of tumor cells, to evaluate the role of apoptosis in p53-mediated biological effects, and to examine the effect of Adenovirus-p53 on the tumorigenicities of the lung cancer cell lines in vitro. Result: The results of our study showed that cells expressing endogenous mutant p53 and those devoid of p53 expression altogether were significantly more sensitive to Adenovirus-p53-mediated cytotoxicity compared to tumor cells expressing endogenous wild-type p53 and that overexpression of wild-type p53 induced programmed cell death. Also we knew that Adenovirus-p53 significantly reduced tumor colony formation of human non-small cell lung cancer cell lines, and decreased the growth of pre-formed colonies in vitro. Conclusion: These results suggest that adenovirus is an efficient vector for mediating transfer and expression of tumor suppressor genes in human non-small cell lung cancer cells and that the tumor cells null for p53 or expressing mutant p53 readily undergo apoptosis by Adenovirus-p53.

• Journal of Gastric Cancer
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• v.3 no.4
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• pp.206-213
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• 2003

Purpose: The clinical implication of p53 mutation in gastric cancer is still unclear, as shown by the discordant results that continue to be reported in the literature. Materials and Methods: To assess p53 gene mutation, tumor p53 overexpression, and serum anti-p53 antibody, we employed a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, an immunohistochemistry using monoclonal antibody DO-7, and an enzymelinked immunosorbent assay (ELISA), respectively. Results: Of 169 surgical specimens of gastric cancer, mutation at exon $5\∼8$ of the p53 was identified in 33 ($19.5\%$) and was significantly correlated with lymph node metastasis. Overexpression of p53 was found in 62 specimens ($36.7\%$) and had a significant correlation with tumor differentiation. Serum anti-p53 antibody was positive in 18 patients ($10.7\%$). Twenty-three of the mutated tumors ($69.7\%$) and 39 of the non-mutated tumors ($28.7\%$) displayed immunoreactivity. Twelve of the immunopositive tumors ($19.4\%$) and 6 of the immunonegative tumors produced anti-p53 antibody. These differences were statistically significant (P<0.001 and P=0.005, respectively). There was no significant difference in survival according to the mutation of p53. Conclusion: Mutation and overexpression of p53 can be easily detected by immunohistochemistry. However, standardization of the immunohistochemical staining method, as well as guidelines for interpreting the stained result, will produce concordant results and thereby improve clinical application.

• Journal of Life Science
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• v.28 no.4
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• pp.488-495
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• 2018

The p53 gene plays a critical role in the transcriptional regulation of cellular response to stress, DNA damage, hypoxia, and tumor development. Keeping in mind the recently discovered manifold physiological functions of p53, its involvement in the regulation of cancer is not surprising. In about 50% of all human cancers, inactivation of p53's protein function occurs either through mutations in the gene itself or defects in the mechanisms that activate it. This disorder plays a crucial role in tumor evolution by allowing the evasion of a p53-dependent response. Many recent studies have focused on directly targeting p53 mutants by identifying selective, small molecular compounds to deplete them or to restore their tumor-suppressive function. These small molecules should effectively regulate various interactions while maintaining good drug-like properties. Among them, the discovery of the key p53-negative regulator, MDM2, has led to the design of new small molecule inhibitors that block the interaction between p53 and MDM2. Some of these small molecule compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, more personalized anti-carcinogenic medicines. Here, we review the structural and functional consequences of wild type and mutant p53 as well as the development of therapeutic agents that directly target this gene, and compounds that inhibit the interaction between it and MDM2.

• Biomedical Science Letters
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• v.29 no.4
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• pp.287-295
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• 2023

Amifostine was developed to protect cells, but it is known to induce cytotoxicity and apoptosis, and the exact mechanism is unknown. In this study, we investigated how the DNA mismatch repair (MMR) system interacts with p53 to prevent apoptosis, cell cycle arrest, and cytoprotective effects induced by amifostine. HCT116 colon cancer cells sublines HCT116/p53+,HCT116/p53+, HCT116/p53-, HCT116/E6 and HCT116+ch3/E6 cells were used for evaluation. Amifostine induced G1 arrest and increased toxicity two-fold in p53- cells regardless of MMR expression. Both G1 cell cycle arrest and induction of p53 protein peaked at 24 h after the start of amifostine exposure. Both G1 cell cycle arrest and induction of p53 protein peaked at 24 h after the start of amifostine exposure. Amifostine induced the expression of p21 protein in both p53+ and p53- cells. As for apoptosis, compared to p53- cells, p53+ cells showed 3.5~4.2 times resistance to amifostine-induced apoptosis. HCT116+E6 with both p53 and MMR loss showed maximum apoptosis at 48 h, and HCT116+ch3/E6HCT116+ch3/E6 with p53 loss showed maximum apoptosis at 24 h. As a result, it was confirmed through in vitro experiments that amifostine-induced G1 cell cycle arrest and apoptosis are mediated through a pathway dependent on MMR and p53 protein.

• Radiation Oncology Journal
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• v.16 no.1
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• pp.1-6
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• 1998

Purpose : To determine the incidence and prognostic effect of p53 expression in patients with advanced supralottic cancer. Materials : Twenty-one cases of total 48 advanced supraglottic cancer patients who received postoperative adjuvant radiation therapy were evaluated by immunohistochemical staining employing p53 monoclonal antibody. Result : Three out of six stage III patients and four out of fifteen stage IV patients showed p53 expression without statistically significant difference (p=0.608). Five year survival rates are $93\%$ in p53 negative, $80\%$ in p53 positive patients and there was no significant difference(p=0.776). p53 expression does not show statistically significant correlation with primary tumor status(p=0.877), lymph node status(p=0.874) and age(p=0.64). Conclusion : There was no statistically significant correlation between traditionally known risk factors and p53 expression.

• Korean Journal of Bronchoesophagology
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• v.4 no.1
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• pp.73-78
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• 1998

The mutation of p53 is the most common genetic alteration found in human cancers and has oncogenic properties. mdm-2 is a recently discoverd that controls the p53 activity by binding of its protein, so negative feedback loop has been suggested in which p53 induces mdm-2 expression. The purpose of this study was to analyze the expression of p53 in leukoplakias, mdm-2 in squamous cell carcinomas, and relationship between p53 and mdm-2 expression in leukoplakias and squamous cell carcinomas. The results were as follows : 1) The p53 was expressed 33.4% in leukoplakias 2) The mdm-2 was expressed 8.3% in leukoplakias and 22.7% in squamous cell carcinomas. 3) The expression rate of p53 was higher in specimens negative for mdm-2 than in specimens positive for mdm-2, but there was not significant relationship between p53 and mdm-2 expression. In conclusion p53 was thought to participate in early phase of oncogenesis, and mdm-2 was thought to have a role as a oncogene in squamous cell carcinoma of head and neck. Though there was not significant relationship between p53 and mdm-2 expression, mdm-2 was thought to inhibit p53 activity.

• Tuberculosis and Respiratory Diseases
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• v.65 no.6
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• pp.487-494
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• 2008

Background: Chromosome 17p allele losses and mutations of p53 gene are the most common genetic abnormalities in lung cancer. The purposes of this study were to evaluate the factors associated with p53 protein overexpression and to evaluate its prognostic value in patients with pathologic stage I non-small cell lung cancer (NSCLC). Methods: This is a retrospective review for the patients who underwent surgical resection at Samsung Medical Center between Jan 2003 and Jun 2004. Immunohistochemical staining for p53 protein was performed on tumor tissues from patients with lung cancer. The p53 overexpression was evaluated in relation to age, sex, smoking history, histology and pathologic stage by univariate and multivariate analyses. The disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) were analyzed using the Kaplan-Meier methods and the differences in DFS, DSS and OS were assessed by using the log-rank tests. Results: A total of 125 patients were included in the analysis and a median frequency of p53 expression in tumor tissue was 10%. The p53 overexpression (${\geq}10%$) was more common in squamous cell carcinoma (66%) than in adenocarcinoma (38%, p=0.002). The p53 overexpression was more common in pathologic stage IB (59%) than in IA (38%, p=0.002). Patients with p53-overexpressing tumor (27 years) smoked more years compared with those without it (20 years, p=0.032). Smoking history ${\geq}25$ pack-years was more common in patients with p53 overexpression (58%) than in those without it (38%, p=0.024). In the multivariate analysis, only histology was significantly associated with p53 overexpression. However, there were no significant differences of DFS, DSS and OS in relation to p53 status. Conclusion: The p53 overexpression was associated with histology, pathologic stage and smoking history in patients with pathologic stage I NSCLC. However, the p53 overexpression was not associated with patient's survival.

• Tuberculosis and Respiratory Diseases
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• v.45 no.2
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• pp.333-340
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• 1998

Background: Lung cancer is the leading cause of cancer over the world. P53 alteration is by far the most common genetic defect in lung cancer. The mutation of p53 protein involves the loss of inhibitory function of p53 related tumor suppressor gene and resultant oncogenesis. The analysis of p53 alterations consists of immunohistochemical stain, PCR based assay, or serologic ELISA (enzyme-linked immunosorbent assay). Methods : Serum levels of p53 mutant protein were measured in 69 cases of lung cancer (adenocarcinoma n=29, epidermoid n=16, small cell n=13, large cell n=1, undifferentiated n=1, undetermined n=9) and 42 controls of respiratory disorders using ELISA. Immunohistochemical stain in tissue was performed using monoclonal antibody of p53 in lung cancer subjects. Results: Both serum p53s in nonsmall cell cancer ($0.28{\pm}0.44ng/ml$) and in small cell cancer ($0.20{\pm}0.14ng/ml$) were not different from controls ($0.34{\pm}0.20ng/ml$). Also there was no significant difference in serum p53 according to tumor stages. P53 immunohistochemical stain showed 50% positivity overall in lung cancer. There were no close correlation between serologic level and positivity of immunohistochemical stain. Conclusion: The serologic determination of p53 mutant protein is thought to have no diagnostic role in lung cancer. Immunohistochemical stain in lung cancer specimen shows 50% positivity.

• BMB Reports
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• v.57 no.6
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• pp.299-304
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• 2024

Upregulation of PRAME (preferentially expressed antigen of melanoma) has been implicated in the progression of a variety of cancers, including melanoma. The tumor suppressor p53 is a transcriptional regulator that mediates cell cycle arrest and apoptosis in response to stress signals. Here, we report that PRAME is a novel repressive target of p53. This was supported by analysis of melanoma cell lines carrying wild-type p53 and human melanoma databases. mRNA expression of PRAME was downregulated by p53 overexpression and activation using DNA-damaging agents, but upregulated by p53 depletion. We identified a p53-responsive element (p53RE) in the promoter region of PRAME. Luciferase and ChIP assays showed that p53 represses the transcriptional activity of the PRAME promoter and is recruited to the p53RE together with HDAC1 upon etoposide treatment. The functional significance of p53 activation-mediated PRAME downregulation was demonstrated by measuring colony formation and p27 expression in melanoma cells. These data suggest that p53 activation, which leads to PRAME downregulation, could be a therapeutic strategy in melanoma cells.