title: The African-specific S47 polymorphism of p53 alters chemosensitivity.
abstract: The TP53 protein is known to affect the sensitivity of tumor cells to cell death by DNA damaging agents. We recently reported that human and mouse cells containing an African-specific coding region variant of p53, Pro47Ser (hereafter S47), are impaired in the transactivation of a small subset of p53 target genes including GLS2 and SCO2, and are markedly resistant to cisplatin. Further, mice containing this variant are markedly predisposed to cancer. Together these findings suggested that cancer-affected humans with the S47 variant might not be effectively treated with cisplatin. To more directly test this premise, we created transformed derivatives of mouse embryo fibroblasts (MEFs) containing wild type p53 (WT) and the S47 variant and analyzed them for chemosensitivity. We find that transformation with E1A and Ras actually reverses the chemosensitivity/transcriptional differences between WT p53 and S47. Specifically, E1A/Ras-transformed S47 cells show increased sensitivity to cisplatin and paclitaxel, and comparable transactivation of GLS2 and SCO2, compared to cells with WT p53. These data suggest that the functional differences between WT p53 and S47 in primary cells may not hold true for transformed cells. They also offer hope that cisplatin and paclitaxel may be effective chemotherapeutic drugs for S47 individuals with cancer.
authors.affiliation: a Program in Molecular and Cellular Oncogenesis, The Wistar Institute , Philadelphia , PA , USA.
authors.forename: Subhasree
authors.initials: S
authors.lastname: Basu
authors.affiliation: a Program in Molecular and Cellular Oncogenesis, The Wistar Institute , Philadelphia , PA , USA.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Barnoud
authors.affiliation: b ICCE Institute and Department of Internal Medicine, Division of Molecular Oncology, Siteman Cancer Center, Washington University School of Medicine , St Louis , MO , USA.
authors.forename: Che-Pei
authors.initials: CP
authors.lastname: Kung
authors.affiliation: a Program in Molecular and Cellular Oncogenesis, The Wistar Institute , Philadelphia , PA , USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Reiss
authors.affiliation: a Program in Molecular and Cellular Oncogenesis, The Wistar Institute , Philadelphia , PA , USA.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D044383:Black People / Q000235:genetics*; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000494:pharmacology; D002999:Clone Cells; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C477224:erastin; D004317:Doxorubicin; D018631:ras Proteins; D017239:Paclitaxel; D002945:Cisplatin
keywords: Gls2; Pro47Ser; Sco2; chemosensitivity; cisplatin; ferroptosis