Abstract
Patients presenting with diffuse large B cell lymphoma (DLBCL) are treated with a standard anthracycline-based chemotherapeutic mixture consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Half of DLBCL patients will develop chemo-refractory tumors due to the emergence of CHOP-resistant DLBCL cells. We isolated DLBCL cells that were resistant to CHOP as a model system to investigate the molecular basis of CHOP resistance. Resistant cells emerged from CHOP-sensitive DLBCL populations after repeated cycles of on-off exposure to stepwise increased dosages of CHOP. A proteomic analysis of CHOP-sensitive and -resistant DLBCL cells identified the zeta isoform of the 14-3-3 family as a differentially expressed protein. CHOP-sensitive cells showed reduced expression of 14-3-3zeta protein in the presence of high-dose CHOP relative to control cells. In contrast, CHOP-resistant cells expressed markedly higher levels of 14-3-3zeta regardless the presence of high-dose CHOP. Because 14-3-3zeta is known to exert anti-apoptotic influences and chemoresistance in lung, colon, and prostate carcinoma, we hypothesized that 14-3-3zeta promotes survival of DLBCL cells in CHOP. In support of our hypothesis, knockdown of 14-3-3zeta by small interfering RNA restored the sensitivity of resistant DLBCL to CHOP-induce apoptosis. In addition, 14-3-3zeta expression was highly up-regulated in a resected DLBCL lymph node relative to a normal lymph node by Western blot analysis. Furthermore, more than half of 35 DLBCL tissues showed elevated 14-3-3zeta expression relative to normal lymph tissue by immunohistochemical analysis. Our study implicates 14-3-3zeta in the pathogenesis of DLBCL and suggests a promising combination strategy with a 14-3-3 inhibitor for the treatment of refractory DLBCL.
Highlights
Diffuse large B-cell lymphoma (DLBCL)2 is one of the most common subtypes of non-Hodgkin lymphoma, accounting for about 30% of all cases [1, 2]
The addition of rituximab to combinatorial CHOP has been accepted as the new standard of treatment, which has resulted in the first major improvement in therapy in more than two decades
In this report we provide evidence for a role of a member of the 14-3-3 family in mediating resistance of DLBCL cells to CHOP. 14-3-3 proteins function in multiple cellular processes including the maintenance of cell cycle checkpoints, DNA repair, and the prevention of apoptosis (4 –7). 14-3-3 is a family of acidic dimeric proteins that are highly conserved and ubiquitously expressed in eukaryotic cells
Summary
With a diffuse growth pattern and a high proliferation fraction. Combinatorial cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy has been the standard systemic therapy for DLBCL with a cure rate of 40 –50%. The dephosphorylation of Bad by phosphatases such as phosphatase 2A that are activated by proapoptotic signals triggers its release from 14-3-3 [11] Another BH3-only protein designated Bim is regulated by 14-3-3 and Akt [12]. Recent clinical data associate 14-3-3 expression with advanced disease grade and poor survival outcome of lung cancer patients [22]. In this manuscript we describe our novel in vitro system to study the process of multidrug chemoresistance in DLBCL. Our observations implicate 14-3-3 as a potential therapeutic target in chemo-refractory DLBCL To our knowledge this is the first report describing a role for a 14-3-3 protein in mediating a multidrug-resistant phenotype in DLBCL
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