title: A role for c-myc in DNA damage-induced apoptosis in a human TP53-mutant small-cell lung cancer cell line.
abstract: Based on the role of p53 in the control of apoptosis following DNA damage, the status of the TP53 gene has been implicated as a major determinant of tumour responsiveness to cytotoxic therapies. In spite of the high frequency of TP53 mutations, small-cell lung cancer (SCLC) is recognised as one of the most chemoresponsive solid tumours. Since the relevance of the TP53 gene status in the modulation of tumour responsiveness is dependent on the molecular/biological context, in the present study, we have examined the relationship between chemosensitivity and susceptibility to apoptosis of a TP53-mutant human SCLC cell line. The cell line, in spite of TP53 mutation, retained an efficient response to genotoxic stress as documented by cells ability to modulate the p53 protein, arrest in the G1 and G2 phases of the cell cycle and its marked susceptibility to apoptosis following treatment with DNA damaging agents. Exposure to DNA-damaging agents caused an increase of c-Myc, a DNA damage-responsive transcription factor. An analysis of damage-induced apoptosis in the presence of an anti-Fas/CD95 inhibitory antibody indicated that Fas/CD95 was not required for the apoptotic response. The results support an implication of c-myc in sensitising cells to apoptosis, since inhibition of c-Myc expression with an antisense oligodeoxynucleotide (AS-ODN) almost abolished the drug-induced apoptotic response. In conclusion, the present results support a role for c-myc in the induction of apoptosis by genotoxic stress in the absence of a functional p53 and provide new insights into the mechanisms that may influence apoptosis in TP53-mutant cells. Elucidation of this pathway and of the possible cooperation with p53-dependent mechanisms may provide a basis for therapeutic intervention.
authors.affiliation: Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Supino
authors.forename: P
authors.initials: P
authors.lastname: Perego
authors.forename: L
authors.initials: L
authors.lastname: Gatti
authors.forename: C
authors.initials: C
authors.lastname: Caserini
authors.forename: C
authors.initials: C
authors.lastname: Leonetti
authors.forename: M
authors.initials: M
authors.lastname: Colantuono
authors.forename: V
authors.initials: V
authors.lastname: Zuco
authors.forename: N
authors.initials: N
authors.lastname: Carenini
authors.forename: G
authors.initials: G
authors.lastname: Zupi
authors.forename: F
authors.initials: F
authors.lastname: Zunino
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004317:Doxorubicin / Q000494:pharmacology; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin