title: α2β1 integrin promotes chemoresistance against doxorubicin in cancer cells through extracellular signal-regulated kinase (ERK).
abstract: The role and the mechanisms by which β1 integrins regulate the survival and chemoresistance of T cell acute lymphoblastic leukemia (T-ALL) still are poorly addressed. In this study, we demonstrate in T-ALL cell lines and primary blasts, that engagement of α2β1 integrin with its ligand collagen I (ColI), reduces doxorubicin-induced apoptosis, whereas fibronectin (Fn) had no effect. ColI but not Fn inhibited doxorubicin-induced mitochondrial depolarization, cytochrome c release, and activation of caspase-9 and -3. ColI but not Fn also prevented doxorubicin from down-regulating the levels of the prosurvival Bcl-2 protein family member Mcl-1. The effect of ColI on Mcl-1 occurred through the inhibition of doxorubicin-induced activation of c-Jun N-terminal kinase (JNK). Mcl-1 knockdown experiments showed that the maintenance of Mcl-1 levels is essential for ColI-mediated T-ALL cell survival. Furthermore, activation of MAPK/ERK, but not PI3K/AKT, is required for ColI-mediated inhibition of doxorubicin-induced JNK activation and apoptosis and for ColI-mediated maintenance of Mcl-1 levels. Thus, our study identifies α2β1 integrin as an important survival pathway in drug-induced apoptosis of T-ALL cells and suggests that its activation can contribute to the generation of drug resistance.
authors.affiliation: Centre de Recherche en Rhumatologie/Immunologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, and Faculté de Médecine, Université Laval, 2705 Boulevard Laurier, Local T1-49, Québec G1V4G2, Canada.
authors.forename: Dalila
authors.initials: D
authors.lastname: Naci
authors.affiliation: Centre de Recherche en Rhumatologie/Immunologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, and Faculté de Médecine, Université Laval, 2705 Boulevard Laurier, Local T1-49, Québec G1V4G2, Canada.
authors.forename: Mohammed-Amine
authors.initials: MA
authors.lastname: El Azreq
authors.affiliation: Centre de Recherche en Rhumatologie/Immunologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, and Faculté de Médecine, Université Laval, 2705 Boulevard Laurier, Local T1-49, Québec G1V4G2, Canada.
authors.forename: Nizar
authors.initials: N
authors.lastname: Chetoui
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, Institut Universitaire d'Hématologie Université Paris Denis Diderot, Hôpital Saint Louis, 75010 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Lauden
authors.affiliation: INSERM U944, Institut Universitaire d'Hématologie Université Paris Denis Diderot, Hôpital Saint Louis, 75010 Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, Institut Universitaire d'Hématologie Université Paris Denis Diderot, Hôpital Saint Louis, 75010 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, Institut Universitaire d'Hématologie Université Paris Denis Diderot, Hôpital Saint Louis, 75010 Paris, France.
authors.forename: Reem
authors.initials: R
authors.lastname: Al-Daccak
authors.affiliation: Centre de Recherche en Rhumatologie/Immunologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, and Faculté de Médecine, Université Laval, 2705 Boulevard Laurier, Local T1-49, Québec G1V4G2, Canada. Electronic address: fawzi.aoudjit@crchul.ulaval.ca.
authors.forename: Fawzi
authors.initials: F
authors.lastname: Aoudjit
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D024042:Collagen Type I; D005353:Fibronectins; D038982:Integrin alpha2beta1; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D004317:Doxorubicin; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D053453:Caspase 9