Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles

Abstract Background p53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other re...

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Main Authors: Stephanie Antoun, David Atallah, Roula Tahtouh, Nada Alaaeddine, Malak Moubarak, Abir Khaddage, Eliane Nasr Ayoub, George Chahine, George Hilal
Format: Article
Language:English
Published: BMC 2018-01-01
Series:Cancer Cell International
Subjects:
Online Access:http://link.springer.com/article/10.1186/s12935-018-0514-2
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author Stephanie Antoun
David Atallah
Roula Tahtouh
Nada Alaaeddine
Malak Moubarak
Abir Khaddage
Eliane Nasr Ayoub
George Chahine
George Hilal
author_facet Stephanie Antoun
David Atallah
Roula Tahtouh
Nada Alaaeddine
Malak Moubarak
Abir Khaddage
Eliane Nasr Ayoub
George Chahine
George Hilal
author_sort Stephanie Antoun
collection DOAJ
description Abstract Background p53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other regions such as the proline rich domain may also affect the protein’s expression and activity. The aim of this study is to investigate the effect of various positions of mutations in TP53 gene on glycolysis, apoptosis and transcription of p53 target genes. Methods Mutations frequency and their effect on p53 expression were assessed by PCR-SSCP, sequencing and immunohistochemistry on 30 ovarian cancer biopsies. Six tumors were cultured, as well as SK-OV-3, OVCAR-3 and Igrov-1. SK-OV-3 cells were transfected with 2 TP53 mutants. p53 transcriptional activity was assayed by qPCR, apoptosis by flow cytometry and glycolysis by glucose and lactate measurements, with quantification of glycolytic enzymes expression. Results Our results showed a high frequency of the P72R mutant, associated with p53 overexpression in the ovarian biopsies. However, P72R mutant cells showed similar apoptosis and glycolysis as WT cells. DNA binding domain mutations decreased the transcriptional activity of the protein and increased glucose consumption and lactate production. Conclusion Despite the overexpression of the P72R mutated protein in the biopsies, it showed a similar apoptotic activity and glucose regulation ability as WT p53. Knowing that p53 expression status is used for chemotherapeutic approaches and prognosis in ovarian cancer, the results obtained highlight the importance of locating TP53 mutations.
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spelling doaj.art-00521658b23741eca70c31bb9bbcae0f2022-12-22T00:48:02ZengBMCCancer Cell International1475-28672018-01-0118111010.1186/s12935-018-0514-2Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profilesStephanie Antoun0David Atallah1Roula Tahtouh2Nada Alaaeddine3Malak Moubarak4Abir Khaddage5Eliane Nasr Ayoub6George Chahine7George Hilal8Cancer and Metabolism Laboratory, Faculty of Medicine, Saint Joseph UniversityObstetrics and Gynecology Department, Hotel-Dieu De France HospitalCancer and Metabolism Laboratory, Faculty of Medicine, Saint Joseph UniversityRegenerative Medicine and Inflammation Laboratory, Faculty of Medicine, Saint Joseph UniversityObstetrics and Gynecology Department, Hotel-Dieu De France HospitalAnatomy and Pathology Department, Hotel-Dieu De France HospitalAnesthesiology Department, Hotel-Dieu De France HospitalOncology Department, Hotel-Dieu De France HospitalCancer and Metabolism Laboratory, Faculty of Medicine, Saint Joseph UniversityAbstract Background p53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other regions such as the proline rich domain may also affect the protein’s expression and activity. The aim of this study is to investigate the effect of various positions of mutations in TP53 gene on glycolysis, apoptosis and transcription of p53 target genes. Methods Mutations frequency and their effect on p53 expression were assessed by PCR-SSCP, sequencing and immunohistochemistry on 30 ovarian cancer biopsies. Six tumors were cultured, as well as SK-OV-3, OVCAR-3 and Igrov-1. SK-OV-3 cells were transfected with 2 TP53 mutants. p53 transcriptional activity was assayed by qPCR, apoptosis by flow cytometry and glycolysis by glucose and lactate measurements, with quantification of glycolytic enzymes expression. Results Our results showed a high frequency of the P72R mutant, associated with p53 overexpression in the ovarian biopsies. However, P72R mutant cells showed similar apoptosis and glycolysis as WT cells. DNA binding domain mutations decreased the transcriptional activity of the protein and increased glucose consumption and lactate production. Conclusion Despite the overexpression of the P72R mutated protein in the biopsies, it showed a similar apoptotic activity and glucose regulation ability as WT p53. Knowing that p53 expression status is used for chemotherapeutic approaches and prognosis in ovarian cancer, the results obtained highlight the importance of locating TP53 mutations.http://link.springer.com/article/10.1186/s12935-018-0514-2ApoptosisGlucose metabolismMutationp53 overexpressionOvarian cancer
spellingShingle Stephanie Antoun
David Atallah
Roula Tahtouh
Nada Alaaeddine
Malak Moubarak
Abir Khaddage
Eliane Nasr Ayoub
George Chahine
George Hilal
Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles
Cancer Cell International
Apoptosis
Glucose metabolism
Mutation
p53 overexpression
Ovarian cancer
title Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles
title_full Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles
title_fullStr Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles
title_full_unstemmed Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles
title_short Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles
title_sort different tp53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles
topic Apoptosis
Glucose metabolism
Mutation
p53 overexpression
Ovarian cancer
url http://link.springer.com/article/10.1186/s12935-018-0514-2
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