14-3-3zeta mediates resistance of diffuse large B cell lymphoma to an anthracycline-based chemotherapeutic regimen. Export

@article{citeulike:5930322, 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.}, author = {Maxwell, Steve A. and Li, Zenggang and Jaya, David and Ballard, Scott and Ferrell, Jay and Fu, Haian}, citeulike-article-id = {5930322}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M109.022418}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19525224}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19525224}, day = {14}, doi = {10.1074/jbc.M109.022418}, issn = {0021-9258}, journal = {The Journal of biological chemistry}, keywords = {biomarker, diffuse\_large\_b\_cell\_lymphoma}, month = {August}, number = {33}, pages = {22379--22389}, posted-at = {2009-10-12 20:15:14}, priority = {2}, title = {14-3-3zeta mediates resistance of diffuse large B cell lymphoma to an anthracycline-based chemotherapeutic regimen.}, url = {http://dx.doi.org/10.1074/jbc.M109.022418}, volume = {284}, year = {2009} }

TY - JOUR ID - citeulike:5930322 L3 - citeulike-article-id:5930322 N2 - 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. IS - 33 JF - The Journal of biological chemistry SN - 0021-9258 EP - 22389 TI - 14-3-3zeta mediates resistance of diffuse large B cell lymphoma to an anthracycline-based chemotherapeutic regimen. VL - 284 SP - 22379 KW - biomarker KW - diffuse_large_b_cell_lymphoma AU - Maxwell, Steve AU - Li, Zenggang AU - Jaya, David AU - Ballard, Scott AU - Ferrell, Jay AU - Fu, Haian PY - 2009/08/14/ UR - http://dx.doi.org/10.1074/jbc.M109.022418 ER -