The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a poor response to treatment and prognosis. Constitutive activation of different signaling pathways in subsets of MCLs, through genetic and/or nongenetic alterations, endows tumor cells with enhanced proliferation and reduced apoptosis. The canonical Wnt pathway (b-catenin/TCF-LEF), implicated in the pathogenesis of numerous cancers, is constitutively active in half of MCLs. Here, we show that ZEB1, a transcription factor better known for promoting metastasis in carcinomas, is expressed in primary MCLs with active Wnt signaling. ZEB1 expression in MCL cells depends on Wnt, being downregulated by b-catenin knockdown or blocking of Wnt signaling by salinomycin. Knockdown of ZEB1 reduces in vitro cell viability and proliferation in MCL cells, and, importantly, tumor growth in mouse xenograft models. ZEB1 activates proliferation-associated (HMGB2, UHRF1, CENPF, MYC, MKI67, and CCND1) and antiapoptotic (MCL1, BCL2, and BIRC5) genes and inhibits pro-apoptotic ones (TP53, BBC3, PMAIP1, and BAX). We show that ZEB1 expression in MCL cells determines differential resistance to chemotherapy drugs and regulates transporters involved in drug influx/efflux. Downregulation of ZEB1 by salinomycin increases the sensitivity of MCL cells to the cytotoxic effect of doxorubicin, cytarabine and gemcitabine. Lastly, salinomycin and doxorubicin display a synergistic effect in established and primary MCL cells. These results identify ZEB1 in MCL where it promotes cell proliferation, enhanced tumor growth and a differential response to chemotherapy drugs. ZEB1 could thus potentially become a predictive biomarker and therapeutic target in this lymphoma.

Lentiviral vector mediated-ASAP1 expression promotes epithelial to mesenchymal transition in ovarian cancer cells

“…EMT is a biological process accompanied by the loss of cell adherence junctions and apical-basal polarity, and acquisition of the mesenchymal phenotype to increase cell motility and invasiveness (5). EMT marker gene expression is altered during the EMT process with downregulation of epithelial markers such as E-cadherin and upregulation of mesenchymal markers, including Snai1 and 2, N-cadherin, vimentin, Zeb 1/2, and Twist1/2 (6,7). ASAP1 (ArfGAP with SH3 Domain, Ankyrin Repeat and PH Domain 1) protein has N-terminal BAR, PH, ARF GAP, ankyrin repeat, proline-rich, and C-terminal SH3 domains (8).…”

Salinomycin: A new paradigm in cancer therapy

“…Salinomycin blocked Wnt signaling and downregulated ZEB1, thereby increasing the sensitivity of MCL cells to the cytotoxic effect of gemcitabine, cytarabine, and doxorubicin. 70 In combination with metformin, salinomycin was able to block TGFβ-induced EMT and inhibit EMT-induced cell migration in the two non-smallcell lung cancer cell lines A549 and HCC4006. 71 Salinomycin inhibited doxorubicin-induced EMT by activation of FOXO3a which disrupted the interaction of β-catenin and TCF and suppressed its downstream targets like ZEB1, CyclinD1, and c-Myc, involved in doxorubicin-induced EMT in hepatocellular carcinoma cells.…”

“…Salinomycin reduced the level of 68 Several studies conducted in vitro as well as in vivo suggest that salinomycin inhibits migratory and invasive potential of cancer cells. 59,[69][70][71][72][73] Salinomycin was able to significantly reduce the metastasis and invasion abilities of bladder cancer cell line T24. Tumor tissues from rats inoculated with T24 cells showed high expression of E-cadherin and lower vimentin expression level in the salinomycin-treated group.…”

Tumour-promoting role of EMT-inducing transcription factor ZEB1 in mantle cell lymphoma

“…3 They found ZEB1 overexpression in half of the samples with a strong correlation with nuclear b-catenin presence (Wnt signalling active). In addition, the clinico-pathological analysis of patient data revealed ZEB1 positivity as a marker for shorter overall survival.…”

“…2 A good example of this is a recent article by Sanchez-Tillo et al that investigated the role of EMT-inducing transcription factor ZEB1 in mantle cell lymphoma (MCL) progression. 3 MCL is a B-cell malignancy and considered as the rarest form of non-Hodgkin lymphoma. 4 Despite this statistical data, it is responsible for a significant portion of B-cell malignancy related mortality because it is an aggressive cancer with a continuous relapse pattern.…”