c-Myc overexpression sensitises colon cancer cells to camptothecin-induced apoptosis

D. Arango, J. M. Mariadason, A. J. Wilson, W. Yang, G. A. Corner, C. Nicholas, M. J. Aranes, Leonard H. Augenlicht

Research output: Contribution to journalArticle

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Abstract

The proto-oncogene c-Myc is overexpressed in 70% of colorectal tumours and can modulate proliferation and apoptosis after cytotoxic insult. Using an isogenic cell system, we demonstrate that c-Myc overexpression in colon carcinoma LoVo cells resulted in sensrtisation to camptothecin-induced apoptosis, thus identifying c-Myc as a potential marker predicting response of colorectal tumour cells to camptothecin. Both camptothecin exposure and c-Myc overexpression in LoVo cells resulted in elevation of p53 protein levels, suggesting a role of p53 in the c-Myc-imposed sensitisation to the apoptotic effects of camptothecin. This was confirmed by the ability of PFT-α, a specific inhibitor of p53, to attenuate camptothecin-induced apoptosis. p53 can induce the expression of p21Waf1/CiP1, an antiproliferative protein that can facilitate DNA repair and drug resistance. Importantly, although camptothecin treatment markedly increased p21Waf1/Cip1 levels in parental LoVo cells, this effect was abrogated in c-Myc-overexpressing derivatives. Targeted inactivation of p21Waf1/Clp1 in HCTI 16 colon cancer cells resulted in significantly increased levels of apoptosis following treatment with camptothecin, demonstrating the importance of p21 Waf1/Cip1 in the response to this agent. Finally, cDNA microarray analysis was used to identify genes that are modulated in expression by c-Myc upregulation that could serve as additional markers predicting response to camptothecin. Thirty-four sequences were altered in expression over four-fold in two isogenic c-Myc-overexpressing clones compared to parental LoVo cells. Moreover, the expression of 10 of these genes was confirmed to be significantly correlated with response to camptothecin in a panel of 30 colorectal cancer cell lines.

Original languageEnglish (US)
Pages (from-to)1757-1765
Number of pages9
JournalBritish Journal of Cancer
Volume89
Issue number9
DOIs
StatePublished - Nov 3 2003

Fingerprint

Camptothecin
Colonic Neoplasms
Apoptosis
Colorectal Neoplasms
myc Genes
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Drug Resistance
DNA Repair
Colon
Proteins
Up-Regulation
Clone Cells
Carcinoma
Gene Expression
Cell Line

Keywords

  • Apoptosis
  • Camptothecin
  • Microarray
  • p21

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Arango, D., Mariadason, J. M., Wilson, A. J., Yang, W., Corner, G. A., Nicholas, C., ... Augenlicht, L. H. (2003). c-Myc overexpression sensitises colon cancer cells to camptothecin-induced apoptosis. British Journal of Cancer, 89(9), 1757-1765. https://doi.org/10.1038/sj.bjc.6601338

c-Myc overexpression sensitises colon cancer cells to camptothecin-induced apoptosis. / Arango, D.; Mariadason, J. M.; Wilson, A. J.; Yang, W.; Corner, G. A.; Nicholas, C.; Aranes, M. J.; Augenlicht, Leonard H.

In: British Journal of Cancer, Vol. 89, No. 9, 03.11.2003, p. 1757-1765.

Research output: Contribution to journalArticle

Arango, D, Mariadason, JM, Wilson, AJ, Yang, W, Corner, GA, Nicholas, C, Aranes, MJ & Augenlicht, LH 2003, 'c-Myc overexpression sensitises colon cancer cells to camptothecin-induced apoptosis', British Journal of Cancer, vol. 89, no. 9, pp. 1757-1765. https://doi.org/10.1038/sj.bjc.6601338
Arango D, Mariadason JM, Wilson AJ, Yang W, Corner GA, Nicholas C et al. c-Myc overexpression sensitises colon cancer cells to camptothecin-induced apoptosis. British Journal of Cancer. 2003 Nov 3;89(9):1757-1765. https://doi.org/10.1038/sj.bjc.6601338
Arango, D. ; Mariadason, J. M. ; Wilson, A. J. ; Yang, W. ; Corner, G. A. ; Nicholas, C. ; Aranes, M. J. ; Augenlicht, Leonard H. / c-Myc overexpression sensitises colon cancer cells to camptothecin-induced apoptosis. In: British Journal of Cancer. 2003 ; Vol. 89, No. 9. pp. 1757-1765.
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