title: Ras puts the brake on doxorubicin-mediated cell death in p53-expressing cells.
abstract: Doxorubicin is one of the most effective molecules used in the treatment of various tumors. Contradictory reports often open windows to understand the role of p53 tumor suppressor in doxorubicin-mediated cell death. In this report, we provide evidences that doxorubicin induced more cell death in p53-negative tumor cells. Several cells, having p53 basal expression, showed increase in p53 DNA binding upon doxorubicin treatment. Doxorubicin induced cell death in p53-positive cells through expression of p53-dependent genes and activation of caspases and caspase-mediated cleavage of cellular proteins. Surprisingly, in p53-negative cells, doxorubicin-mediated cell death was more aggressive (faster and intense). Doxorubicin increased the amount of Fas ligand (FasL) by enhancing activator protein (AP) 1 DNA binding in both p53-positive and p53-negative cells, but the basal expression of Fas was higher in p53-negative cells. Anti-FasL antibody considerably protected doxorubicin-mediated cell death in both types of cells. Activation of caspases was faster in p53-negative cells upon doxorubicin treatment. In contrast, the basal expression of Ras oncoprotein was higher in p53-positive cells, which might increase the basal expression of Fas in these cells. Overexpression of Ras decreased the amount of Fas in p53-negative cells, thereby decreasing doxorubicin-mediated aggressive cell death. Overall, this study will help to understand the much studied chemotherapeutic drug, doxorubicin-mediated cell signaling cascade, that leads to cell death in p53-positive and -negative cells. High basal expression of Fas might be an important determinant in doxorubicin-mediated cell death in p53-negative cells.
authors.affiliation: Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500 001, India. manna@cdfd.org.in
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Manna
authors.forename: Charitha
authors.initials: C
authors.lastname: Gangadharan
authors.forename: Damodar
authors.initials: D
authors.lastname: Edupalli
authors.forename: Nune
authors.initials: N
authors.lastname: Raviprakash
authors.forename: Thota
authors.initials: T
authors.lastname: Navneetha
authors.forename: Sidharth
authors.initials: S
authors.lastname: Mahali
authors.forename: Maikho
authors.initials: M
authors.lastname: Thoh
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001943:Breast Neoplasms; D020169:Caspases / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020298:U937 Cells; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016328:NF-kappa B; C495901:TP53 protein, human; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D018631:ras Proteins