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

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 sensitisation 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-alpha, a specific inhibitor of p53, to attenuate camptothecin-induced apoptosis. p53 can induce the expression of p21(Waf1/Cip1), an antiproliferative protein that can facilitate DNA repair and drug resistance. Importantly, although camptothecin treatment markedly increased p21(Waf1/Cip1) levels in parental LoVo cells, this effect was abrogated in c-Myc-overexpressing derivatives. Targeted inactivation of p21(Waf1/Cip1) in HCT116 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.

• Authors: D Arango, J M Mariadason, A J Wilson, W Yang, G A Corner, C Nicholas, M J Aranes, L H Augenlicht
• Journal: British journal of cancer (Br J Cancer) Vol. 89 Issue 9 Pg. 1757-65 (Nov 03 2003) ISSN: 0007-0920 [Print] England
• PMID: 14583781 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents, Phytogenic
• Biomarkers, Tumor
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• MAS1 protein, human
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-myc
• Camptothecin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects, genetics)
• Biomarkers, Tumor (analysis)
• Blotting, Western
• Camptothecin (pharmacology)
• Cell Line, Tumor
• Colonic Neoplasms (metabolism, pathology)
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (biosynthesis, drug effects)
• Fibroblasts
• Gene Expression Regulation, Neoplastic
• Humans
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-myc (biosynthesis, genetics)