Altered expression of cell proliferation-related and interferon-stimulated genes in colon cancer cells resistant to SN38

• Published in: Cancer biology & therapy Vol. 7; no. 6; pp. 822 - 832
• Main Authors: Gongora, Céline, Candeil, Laurent, Vezzio, Nadia, Copois, Virginie, Denis, Vincent, Bareil, Corinne, Molina, Franck M., Fraslon, Caroline, Conseiller, Emmanuel, Pau, Bernard, Martineau, Pierre, Del Rio, Maguy
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.06.2008
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Binding; Biochemistry, Molecular Biology; Biology; Bioscience; Calcium; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cancer; Cell; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Cycle; DNA Topoisomerases, Type I - metabolism; Drug Resistance, Neoplasm; Genomics; Humans; Inhibitory Concentration 50; Interferons - metabolism; Irinotecan; Landes; Life Sciences; Oligonucleotide Array Sequence Analysis; Organogenesis; Proteins; Time Factors
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.7.6.5838

Irinotecan is a topoisomerase I inhibitor widely used as an anticancer agent in the treatment of metastatic colon cancer. However, its efficacy is often limited by the development of resistance. We have isolated a colon carcinoma cell line, HCT116-SN6, which displays a 6-fold higher resistance to SN38, the active metabolite of irinotecan. In this paper, we studied the molecular mechanisms that cause resistance to SN38 in the HCT116-SN6 cell line. First, we analyzed proliferation, cell cycle distribution, apoptosis, topoisomerase I expression and activity in SN38-resistant (HCT116-SN6) and sensitive (HCT116-s cells). We showed that the SN38-induced apoptosis and the SN38-activated cell cycle checkpoints leading to G2/M cell cycle arrest were similar in both cell lines. Topoisomerase I expression and catalytic activity were also unchanged. Then, we compared mRNA expression profiles in the two cell lines using the Affymetrix Human Genome GeneChip® arrays U133A and B. Microarray analysis showed that among the genes, which were differentially expressed in HCT116-s and HCT116-SN6 cells, 27% were related to cell proliferation suggesting that proliferation might be the main target in the development of resistance to SN38. This result correlates with the phenotypic observation of a reduced growth rate in HCT116-SN6 resistant cells. Furthermore, 29% of the over-expressed genes were Interferon Stimulated Genes and we demonstrate that their over-expression is, at least partially, due to endogenous activation of the p38 MAP kinase pathway in SN38 resistant cells. In conclusion, a slower cell proliferation rate may be a major cause of acquired resistance to SN38 via a reduction of cell cycle progression through the S phase which is mandatory for the cytotoxic action of SN38. This lower growth rate could be due to the endogenous activation of p38.