14-3-3zeta mediates resistance of diffuse large B cell lymphoma to an anthracycline-based chemotherapeutic regimen.
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.
Maxwell
Steve A
SA
Department of Molecular and Cellular Medicine, The Texas A&M Health Science Center, College Station, Texas 77840-1114.
Li
Zenggang
Z
Department of Pharmacology, Emory School of Medicine, Atlanta, Georgia 30322.
Jaya
David
D
Department of Pharmacology, Emory School of Medicine, Atlanta, Georgia 30322.
Ballard
Scott
S
Department of Molecular and Cellular Medicine, The Texas A&M Health Science Center, College Station, Texas 77840-1114.
Ferrell
Jay
J
Department of Molecular and Cellular Medicine, The Texas A&M Health Science Center, College Station, Texas 77840-1114.
Fu
Haian
H
Department of Pharmacology, Emory School of Medicine, Atlanta, Georgia 30322.
D048948:14-3-3 Proteins / Q000378:metabolism*; D018943:Anthracyclines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002469:Cell Separation; D003520:Cyclophosphamide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use; D015180:Electrophoresis, Gel, Two-Dimensional; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism*; D010641:Phenotype; D011239:Prednisolone / Q000627:therapeutic use; D014750:Vincristine / Q000627:therapeutic use
D048948:14-3-3 Proteins; D018943:Anthracyclines; D000970:Antineoplastic Agents; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone