A role for c-myc in DNA damage-induced apoptosis in a human TP53-mutant small-cell lung cancer cell line

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 t umour responsiveness to cytotoxic therapies. In spite of the high frequency of TP53 mutations, small-cell lung cancer (SCLC) is recognised as one of t he most chemoresponsive solid tumours. Since the relevance of the TP53 gene status in the modulation of tumour responsiveness is dependent on the mole cular/biological context, in the present study, we have examined the relati onship between chemosensitivity and susceptibility to apoptosis of a TP53-m utant human SCLC cell line. The cell line, in spite of TP53 mutation, retai ned an efficient response to genotoxic stress as documented by cells abilit y to modulate the p53 protein, arrest in the G1 and G2 phases of the cell c ycle and its marked susceptibility to apoptosis following treatment with DN A damaging agents. Exposure to DNA-damaging agents caused an increase of c- Myc, a DNA damage-responsive transcription factor. An analysis of damage-in duced apoptosis in the presence of an anti-Fas/CD95 inhibitory antibody ind icated that Fas/CD95 was not required for the apoptotic response. The resul ts support an implication of c-mye in sensitising cells to apoptosis, since inhibition of c-Myc expression with an antisense oligodeoxynucteotide (AS- ODN) almost abolished the drug-induced apoptotic response. In conclusion, t he present results support a role for c-mye in the induction of apoptosis b y genotoxic stress in the absence of a functional p53 and provide new insig hts into the mechanisms that may influence apoptosis in TP53-mutant cells. Elucidation of this pathway and of the possible cooperation with p53-depend ent mechanisms may provide a basis for therapeutic intervention. (C) 2001 P ublished by Elsevier Science Ltd. All rights reserved.