title: Rituximab activates Syk and AKT in CD20-positive B cell lymphoma cells dependent on cell membrane cholesterol levels.
abstract: 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.
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nozaki
authors.forename: Toru
authors.initials: T
authors.lastname: Mitsumori
authors.forename: Takeo
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawashima
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shobu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hamanaka
authors.forename: Kei
authors.initials: K
authors.lastname: Nakajima
authors.forename: Norio
authors.initials: N
authors.lastname: Komatsu
authors.forename: Keita
authors.initials: K
authors.lastname: Kirito
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000069283:Rituximab; D000072377:Syk Kinase
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D008563:Membrane Lipids; D000069283:Rituximab; D002784:Cholesterol; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051057:Proto-Oncogene Proteins c-akt