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

R. Supino, P. Perego, L. Gatti, C. Caserini, C. Leonetti, M. Colantuono, V. Zuco, N. Carenini, G. Zupi, F. Zunino

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2247-2256
Number of pages10
JournalEuropean Journal of Cancer
Volume37
Issue number17
DOIs
Publication statusPublished - 2001

Fingerprint

Small Cell Lung Carcinoma
DNA Damage
Apoptosis
Cell Line
p53 Genes
Neoplasms
Oligodeoxyribonucleotides
G2 Phase
DNA
G1 Phase
Mutation Rate
Cell Cycle
Transcription Factors
Mutation
Antibodies
Therapeutics
Pharmaceutical Preparations
Proteins

Keywords

  • Apoptosis
  • c-myc
  • DNA damage
  • Small-cell lung cancer
  • TP53-mutation

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

A role for c-myc in DNA damage-induced apoptosis in a human TP53-mutant small-cell lung cancer cell line. / Supino, R.; Perego, P.; Gatti, L.; Caserini, C.; Leonetti, C.; Colantuono, M.; Zuco, V.; Carenini, N.; Zupi, G.; Zunino, F.

In: European Journal of Cancer, Vol. 37, No. 17, 2001, p. 2247-2256.

Research output: Contribution to journalArticle

Supino, R. ; Perego, P. ; Gatti, L. ; Caserini, C. ; Leonetti, C. ; Colantuono, M. ; Zuco, V. ; Carenini, N. ; Zupi, G. ; Zunino, F. / A role for c-myc in DNA damage-induced apoptosis in a human TP53-mutant small-cell lung cancer cell line. In: European Journal of Cancer. 2001 ; Vol. 37, No. 17. pp. 2247-2256.
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AU - Perego, P.

AU - Gatti, L.

AU - Caserini, C.

AU - Leonetti, C.

AU - Colantuono, M.

AU - Zuco, V.

AU - Carenini, N.

AU - Zupi, G.

AU - Zunino, F.

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AB - 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.

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