The introduction of
rituximab, an anti-CD20
monoclonal antibody, has dramatically improved the treatment outcomes of patients with
B cell lymphoma. Nevertheless, the clinical response to
rituximab varies, and a subpopulation of patients does not respond well to this antibody. Although several molecular events have been shown to be involved in the mechanism of action of
rituximab, recent studies have demonstrated that intracellular signaling pathways and the direct effects of
rituximab on cell membrane components are responsible for the antilymphoma action of this
drug. In the present study, we demonstrated that
rituximab activated Syk and Akt, molecules with antiapoptotic functions, in several CD20-positive
lymphoma cell lines. Notably,
rituximab activated Syk and Akt in all the tested primary
lymphoma samples from six patients. Our results show that the
cholesterol levels in
lymphoma cell membranes have a crucial role in the regulation of Syk and Akt. The depletion of
cholesterol from the cell membrane completely blocked
rituximab-induced Syk and Akt activation.
Simvastatin, an inhibitor of
cholesterol synthesis, also abrogated
rituximab-mediated Syk and Akt activation. Finally, we report that
rituximab inhibited the apoptosis induced by chemotherapeutic drugs, which was observed solely in Akt-activated cells. This work demonstrates for the first time that
rituximab paradoxically works to suppress apoptosis under certain conditions in a manner that is dependent on the cell membrane
cholesterol level. Our observations provide novel insights and suggest that the cell membrane
cholesterol level represents a new
biomarker for predicting patient response to
rituximab. Furthermore, the modulation of
lipid rafts could provide a new strategy for enhancing the antilymphoma action of
rituximab.