title: Persistent activation of the Fyn/ERK kinase signaling axis mediates imatinib resistance in chronic myelogenous leukemia cells through upregulation of intracellular SPARC.
abstract: SPARC is an extracellular matrix protein that exerts pleiotropic effects on extracellular matrix organization, growth factor availability, cell adhesion, differentiation, and immunity in cancer. Chronic myelogenous leukemia (CML) cells resistant to the BCR-ABL inhibitor imatinib (IM-R cells) were found to overexpress SPARC mRNA. In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)-resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels of SPARC mRNA were documented in blood cells from CML patients after 1 year of imatinib therapy compared with initial diagnosis. Taken together, our results highlight an important role for the Fyn/ERK signaling pathway in imatinib-resistant cells that is driven by accumulation of intracellular SPARC.
authors.affiliation: Université de Nice Sophia Antipolis, Nice, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Fenouille
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.forename: Maeva
authors.initials: M
authors.lastname: Dufies
authors.forename: Guillaume
authors.initials: G
authors.lastname: Robert
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Mickaël
authors.initials: M
authors.lastname: Ohanna
authors.forename: Marcel
authors.initials: M
authors.lastname: Deckert
authors.forename: Jean-Max
authors.initials: JM
authors.lastname: Pasquet
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.forename: Jill-Patrice
authors.initials: JP
authors.lastname: Cassuto
authors.forename: Sophie
authors.initials: S
authors.lastname: Raynaud
authors.forename: Sophie
authors.initials: S
authors.lastname: Tartare-Deckert
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D042541:Intracellular Space / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D015676:Osteonectin; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D048049:Extracellular Signal-Regulated MAP Kinases