Enhancement of mdr1 gene expression by transforming growth factor-β1 in the new adriamycin-resistant human leukemia cell line ME-F2/ADM

Utsunomiya, Y; Hasegawa, Hitoshi; Yanagisawa, Kohsuke; Fujita, Shigeru

doi:10.1038/sj.leu.2400663

Cited by 8 publications

(4 citation statements)

References 5 publications

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“…Dohgu et al [34] showed that TGF-b1 upregulated P-glycoprotein of brain microvascular endothelial cells. The increased expression of P-glycoprotein together with TGF-bRII in the BBB-damaged vessels of SHRSP is compatible with these findings reported previously [33,34].…”

Section: Discussionsupporting

confidence: 92%

“…In addition, results recently reported indicated that the expression of transforming growth factor-b receptor II (TGF-bRII) was increased in the hippocampal samples of SHRSP, compared with that in the samples of WKY rats [10]. It is known that TGFb increases mdr1 gene expression in a new adriamycin-resistant human leukaemia cell line [33]. Dohgu et al [34] showed that TGF-b1 upregulated P-glycoprotein of brain microvascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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The expression of P‐glycoprotein is increased in vessels with blood‐brain barrier impairment in a stroke‐prone hypertensive model

Ueno¹,

Nakagawa

Huang³

et al. 2009

Neuropathology Appl Neurobio

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The expression of P‐glycoprotein is increased in vessels with blood‐brain barrier impairment in a stroke‐prone hypertensive model

Ueno¹,

Nakagawa

Huang³

et al. 2009

Neuropathology Appl Neurobio

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“…Like CR-1, MDR1 is also a target of HIF [ 46 ] and β-catenin [ 47 ]. TGF-β also induces expression of MDR1 [ 48 ] and crosstalk exists between TGF-β/SMAD2/3 and β-catenin pathways [ 49 ]. Further, AP-1 also controls expression of MDR1 [ 50 ] and it is also known that SMAD interacts with AP-1 [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Autoregulation and Heterogeneity in Expression of Human Cripto-1

et al. 2015

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Cripto-1 (CR-1) is involved in various processes in embryonic development and cancer. Multiple pathways regulate CR-1 expression. Our present work demonstrates a possible positive feedback circuit where CR-1 induces its own expression. Using U-87 MG cells treated with exogenous CR-1, we show that such induction involves ALK4/SMAD2/3 pathway. Stochasticity in gene expression gives rise to heterogeneity in expression in genetically identical cells. Positive feedback increases such heterogeneity and often gives rise to two subpopulations of cells, having higher and lower expression of a gene. Using flow cytometry, we show that U-87 MG cells have a minuscule subpopulation with detectable expression of CR-1. Induction of CR-1 expression, by exogenous CR-1, increases the size of this CR-1 positive subpopulation. However, even at very high dose, most of the cells remain CR-1 negative. We show that population behavior of CR-1 induction has a signature similar to bimodal expression expected in a transcriptional circuit with positive feedback. We further show that treatment of U-87 MG cells with CR-1 leads to higher expression of drug efflux protein MDR-1 in the CR-1 positive subpopulation, indicating correlated induction of these two proteins. Positive feedback driven heterogeneity in expression of CR-1 may play crucial role in phenotypic diversification of cancer cells.

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“…The contribution of TGF-β1 to multidrug resistance is presently unclear. An absence of correlation between TGF-β1 levels and multidrug resistance was reported in chronic lymphocytic leukaemia [ 23 ] and an enhancement of MDR1 gene expression was described in a human leukaemia cell line [ 24 ]. In contrast, MRP1 and MDR1 and BCL-xL have been previously reported to be upregulated by NF-κB [ 25 – 27 ].…”

Section: Resultsmentioning

confidence: 99%

Nuclear factor-κB activation by transforming growth factor-β1 drives tumour microenvironment-mediated drug resistance in neuroblastoma

Louault,

Blavier,

Lee

et al. 2024

Br J Cancer

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Background Intrinsic and extrinsic factors in the tumour microenvironment (TME) contribute to therapeutic resistance. Here we demonstrate that transforming growth factor (TGF)-β1 produced in the TME increased drug resistance of neuroblastoma (NB) cells. Methods Human NB cell lines were tested in vitro for their sensitivity to Doxorubicin (DOX) and Etoposide (ETOP) in the presence of tumour-associated macrophages (TAM) and mesenchymal stromal cells/cancer-associated fibroblasts (MSC/CAF). These experiments were validated in xenotransplanted and primary tumour samples. Results Drug resistance was associated with an increased expression of efflux transporter and anti-apoptotic proteins. Upregulation was dependent on activation of nuclear factor (NF)-κB by TGF-β-activated kinase (TAK1) and SMAD2. Resistance was reversed upon pharmacologic and genetic inhibitions of NF-κB, and TAK1/SMAD2. Interleukin-6, leukaemia inhibitory factor and oncostatin M were upregulated by this TGF-β/TAK1/NF-κB/SMAD2 signalling pathway contributing to drug resistance via an autocrine loop activating STAT3. An analysis of xenotransplanted NB tumours revealed an increased presence of phospho (p)-NF-κB in tumours co-injected with MSC/CAF and TAM, and these tumours failed to respond to Etoposide but responded if treated with a TGF-βR1/ALK5 inhibitor. Nuclear p-NF-κB was increased in patient-derived tumours rich in TME cells. Conclusions The data provides a novel insight into a targetable mechanism of environment-mediated drug resistance.

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Enhancement of mdr1 gene expression by transforming growth factor-β1 in the new adriamycin-resistant human leukemia cell line ME-F2/ADM

Cited by 8 publications

References 5 publications

The expression of P‐glycoprotein is increased in vessels with blood‐brain barrier impairment in a stroke‐prone hypertensive model

The expression of P‐glycoprotein is increased in vessels with blood‐brain barrier impairment in a stroke‐prone hypertensive model

Autoregulation and Heterogeneity in Expression of Human Cripto-1

Nuclear factor-κB activation by transforming growth factor-β1 drives tumour microenvironment-mediated drug resistance in neuroblastoma

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