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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Fenouille N,Puissant A,Dufies M,Robert G,Jacquel A,Ohanna M,Deckert M,Pasquet JM,Mahon FX,Cassuto JP,Raynaud S,Tartare-Deckert S,Auberger Pdoi
10.1158/0008-5472.CAN-10-2034subject
Has Abstractpub_date
2010-12-01 00:00:00pages
9659-70issue
23eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-2034journal_volume
70pub_type
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