Anomalous constitutive Src kinase activity promotes B lymphoma survival and growth
Previously we have shown that B cell receptor (BCR) expression and B cell receptor signaling pathways are important for the basal growth of B lymphoma cells. In particular we have shown that the activation of Syk, a non-src family protein tyrosine kinase (SFK) and the mitogen activated protein (MAP), ERK and JNK that mediate BCR signals kinases is required for the constitutive growth of B lymphoma cells.
Since SFKs like Lyn are known to be needed for the phosphorylation of BCR co-receptors, Ig-a and Ig-b, we hypothesized that one or more SFKs will be constitutively activated in B lymphoma cells and may be necessary for B lymphoma growth.
Results: Src kinase activity was found to be constitutively high in many murine and human B lymphoma cell lines and primary lymphoma samples. The specific pharmacological inhibitors of Src Family Kinases (SFKs), PP1 and PP2 inhibited the proliferation of a number of both murine and human B lymphomas in a dose-dependent manner.
Importantly, Dasatinib (BMS-354825), an oral dual BCR-ABL and SFK specific inhibitor inhibited the growth of B lymphomas in the nanomolar range in vitro and strongly inhibited a mouse lymphoma growth in vivo. Among the SFKs, Lyn is predominantly phosphorylated and Lyn-specific small interfering RNA inhibited the growth of B lymphomas, supporting an important role for Lyn in B lymphoma growth.
Suppression of SFK activity blocks BCR mediated signaling pathways. PMA or CpG can partially reverse the growth inhibition induced by SFK inhibition.
Although blocking SFK activity inhibited the growth of a number of B lymphomas, some lymphomas such as SudHL-4, SudHL-6, OCI-Ly3 and OCILy10 are more resistant due to an increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL.
Conclusions: These studies further support our concept that BCR signaling pathways are important for the continued growth of established B lymphoma cells. Some of the intermediates in this BCR pathway are potential immunotherapeutic targets.
In particular, inhibition of SFK activity alone or in synergy with inhibition of the prosurvival Bcl-2 proteins holds promise in developing more effective treatments for B lymphoma patients.
Author: Jiyuan KeR ChelvarajanVishal SindhavaDarrell RobertsonLazaros LekakisC JenningsSubbarao Bondada
Credits/Source: Molecular Cancer 2009, 8:132
Published on: 2009-12-31
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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