Src tyrosine kinase regulates adhesion and chemotaxis in Waldenstrom macroglobulinemia.
OBJECTIVE
Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma characterized by widespread involvement of the bone marrow. Despite different options of therapy, Waldenstrom macroglobulinemia is still incurable. Src tyrosine kinase has been shown to play a central role in the regulation of a variety of biological processes, such as cell proliferation, migration, adhesion, and survival in solid tumors. We sought to determine whether the protein tyrosine kinase Src regulates adhesion, migration, and survival in Waldenstrom macroglobulinemia.


METHODS
We tested the expression of Src tyrosine kinase in Waldenstrom macroglobulinemia and normal cells, and the effect of the specific Src inhibitor AZD0530 on the adhesion, migration, cell cycle, and survival of a Waldenstrom macroglobulinemia cell line and patient samples. Moreover, we tested the effect of AZD0530 on cytoskeletal and cell cycle signaling in Waldenstrom macroglobulinemia.


RESULTS
We show that Src is overexpressed in Waldenstrom macroglobulinemia cells compared with control B cells, and that the use of the Src inhibitor AZD0530 led to significant inhibition of adhesion, migration, and cytoskeletal signaling induced by SDF1. Moreover, inhibition of Src activity induced G(1) cell cycle arrest; however, it had minimal effect on survival of Waldenstrom macroglobulinemia cells, and no significant effect on survival of normal cells.


CONCLUSIONS
Taken together, these results delineate the role of Src kinase activity in Waldenstrom macroglobulinemia and provide the framework for future clinical trials using Src inhibitors in combination with other drugs to improve the outcome of patients with Waldenstrom macroglobulinemia.
Ngo
Hai T
HT
Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Azab
Abdel Kareem
AK
Farag
Mena
M
Jia
Xiaoying
X
Melhem
Molly M
MM
Runnels
Judith
J
Roccaro
Aldo M
AM
Azab
Feda
F
Sacco
Antonio
A
Leleu
Xavier
X
Anderson
Kenneth C
KC
Ghobrial
Irene M
IM
D052117:Benzodioxoles / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015688:Oncogene Protein pp60(v-src) / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D008258:Waldenstrom Macroglobulinemia / Q000378:metabolism / Q000473:pathology*
D052117:Benzodioxoles; D054377:Chemokine CXCL12; D003603:Cytotoxins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D015688:Oncogene Protein pp60(v-src)