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 language | English (US) |
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Pages (from-to) | 1757-1765 |
Number of pages | 9 |
Journal | British Journal of Cancer |
Volume | 89 |
Issue number | 9 |
DOIs | |
State | Published - Nov 3 2003 |
Keywords
- Apoptosis
- Camptothecin
- Microarray
- p21
ASJC Scopus subject areas
- Oncology
- Cancer Research