title: Altered expression of cell proliferation-related and interferon-stimulated genes in colon cancer cells resistant to SN38.
abstract: 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 G(2)/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 overexpressed genes were Interferon Stimulated Genes and we demonstrate that their overexpression 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.
authors.affiliation: CNRS, UMR 5160, CRCM, Montpellier, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Gongora
authors.forename: Laurent
authors.initials: L
authors.lastname: Candeil
authors.forename: Nadia
authors.initials: N
authors.lastname: Vezzio
authors.forename: Virginie
authors.initials: V
authors.lastname: Copois
authors.forename: Vincent
authors.initials: V
authors.lastname: Denis
authors.forename: Corinne
authors.initials: C
authors.lastname: Breil
authors.forename: Franck
authors.initials: F
authors.lastname: Molina
authors.forename: Caroline
authors.initials: C
authors.lastname: Fraslon
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Conseiller
authors.forename: Bernard
authors.initials: B
authors.lastname: Pau
authors.forename: Pierre
authors.initials: P
authors.lastname: Martineau
authors.forename: Maguy
authors.initials: M
authors.lastname: Del Rio
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D007372:Interferons / Q000378:metabolism*; D000077146:Irinotecan; D020411:Oligonucleotide Array Sequence Analysis; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D007372:Interferons; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin