Altered expression of cell proliferation-related and interferon-stimulated genes in colon cancer cells resistant to SN38
| Autor: | Céline Gongora, Laurent Candeil, Nadia Vezzio, Virginie Copois, Vincent Denis, Corinne Bareil, Franck M. Molina, Caroline Fraslon, Emmanuel Conseiller, Bernard Pau, Pierre Martineau, Maguy Del Rio |
|---|---|
| Přispěvatelé: | Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut d'histoire moderne et contemporaine (IHMC), Université Paris 1 Panthéon-Sorbonne (UP1)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, Service d'Oncologie Digestive & Département d'Oncologie, Sanofi Aventis, Sanofi-Aventis, Centre National de la Recherche Scientifique (CNRS), Sanofi recherche, SANOFI Recherche, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Paris 1 Panthéon-Sorbonne (UP1)-École normale supérieure - Paris (ENS Paris), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Cell cycle checkpoint Time Factors Cell Survival [SDV]Life Sciences [q-bio] Apoptosis [SDV.CAN]Life Sciences [q-bio]/Cancer Biology Irinotecan 03 medical and health sciences Inhibitory Concentration 50 0302 clinical medicine Interferon Cell Line Tumor [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] medicine Cytotoxic T cell Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology 030304 developmental biology Cell Proliferation Oligonucleotide Array Sequence Analysis Pharmacology 0303 health sciences Cell growth Cell Cycle Cell cycle Molecular biology Antineoplastic Agents Phytogenic digestive system diseases 3. Good health Oncology DNA Topoisomerases Type I Cell culture Drug Resistance Neoplasm 030220 oncology & carcinogenesis Colonic Neoplasms Molecular Medicine Camptothecin Interferons medicine.drug |
| Zdroj: | Cancer Biology and Therapy Cancer Biology and Therapy, Taylor & Francis, 2014, 7 (6), pp.822-832. ⟨10.4161/cbt.7.6.5838⟩ |
| ISSN: | 1538-4047 |
| DOI: | 10.4161/cbt.7.6.5838⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|