14-3-3ζ Mediates Resistance of Diffuse Large B Cell Lymphoma to an Anthracycline-based Chemotherapeutic Regimen

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 isoform of the 14-3-3 family as a differentially expressed protein. CHOP-sensitive cells showed reduced expression of 14-3-3 protein in the presence of high-dose CHOP relative to control cells. In contrast, CHOP-resistant cells expressed markedly higher levels of 14-3-3 regardless the presence of high-dose CHOP. Because 14-3-3 is known to exert anti-apoptotic influences and chemoresistance in lung, colon, and prostate carcinoma, we hypothesized that 14-3-3 promotes survival of DLBCL cells in CHOP. In support of our hypothesis, knockdown of 14-3-3 by small interfering RNA restored the sensitivity of resistant DLBCL to CHOP-induce apoptosis. In addition, 14-3-3 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 14-3-3 expression relative to normal lymph tissue by immunohistochemical analysis. Our study implicates 14-3-3 in the pathogenesis of DLBCL and suggests a promising combination strategy with a 14-3-3 inhibitor for the treatment of refractory DLBCL.

Small Interfering RNA Targeting 14-3-3ζ Increases Efficacy of Chemotherapeutic Agents in Head and Neck Cancer Cells

“…Perhaps most importantly, our results showed that knocking down the expression of 14-3-3ζ in head and neck cancer cells enhanced the efficacy of CT. In support of our data, recent reports have shown similar results in lung cancer, breast cancer, gliomas, and B-cell lymphoma, independently suggesting a role of 14-3-3ζ in cell cycle progression and inhibition of apoptosis (18,33,34). Targeting 14-3-3ζ sensitized lung cancer cells to cisplatin treatment (33), and breast cancer cells (MCF7) to treatment with 5-FU and doxorubicin (19).…”

“…Knocking down 14-3-3ζ expression sensitized chemorefractory diffuse B-cell lymphoma to an anthracycline-based chemotherapeutic cocktail consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; ref. 34). Chatterjee et al (35) showed a novel role of 14-3-3ζ in mediating resistance of prostate cancer cells (DU-145) to topoisomerase I inhibitor, 9-nitrocamptothecin.…”

Reversible Epigenetic Regulation of 14-3-3σ Expression in Acquired Gemcitabine Resistance by Uhrf1 and DNA Methyltransferase 1

“…Although some of the other members of the 14-3-3 protein family, such as 14-3-3z and 14-3-3u/t, have been reported to also contribute to (Maxwell et al, 2009;Neal et al, 2009) and associate with (Hodgkinson et al, 2012) drug resistance, we did not find upregulation in expression of 14-3-3z and 14-3-3u/t in the gemcitabine-resistant G3K cells. This observation suggests that 14-3-3z and 14-3-3u/t may not participate in the acquired gemcitabine resistance in PDAC.…”

Metabolic-Stress-Induced Rearrangement of the 14-3-3ζ Interactome Promotes Autophagy via a ULK1- and AMPK-Regulated 14-3-3ζ Interaction with Phosphorylated Atg9

“…14-3-3 (gene symbol YWHAZ) protects cells from numerous stresses, including chemotherapy-induced death, anoikis, and growth factor deprivation (2)(3)(4)(5)(6). Furthermore, 14-3-3 expression is upregulated in many cancers, and high-level expression has been shown to correlate with poor clinical outcomes in breast cancer (4,5,7,8).…”