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, L. H. Augenlicht

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59 Scopus citations

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
Publication statusPublished - Nov 3 2003

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Keywords

  • Apoptosis
  • Camptothecin
  • Microarray
  • p21

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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