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Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance

Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell-autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)-β-dependent signals from bone...

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Published in:Science translational medicine 2020-01, Vol.12 (526)
Main Authors: Park, Eugene, Chen, Jingyu, Moore, Andrew, Mangolini, Maurizio, Santoro, Antonella, Boyd, Joseph R, Schjerven, Hilde, Ecker, Veronika, Buchner, Maike, Williamson, James C, Lehner, Paul J, Gasparoli, Luca, Williams, Owen, Bloehdorn, Johannes, Stilgenbauer, Stephan, Leitges, Michael, Egle, Alexander, Schmidt-Supprian, Marc, Frietze, Seth, Ringshausen, Ingo
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cited_by cdi_FETCH-LOGICAL-c460t-3053baa0b644a1dcad6ce97e02a43bafc9b9db7fd3ae277080a093fe001bf9313
cites cdi_FETCH-LOGICAL-c460t-3053baa0b644a1dcad6ce97e02a43bafc9b9db7fd3ae277080a093fe001bf9313
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container_issue 526
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container_title Science translational medicine
container_volume 12
creator Park, Eugene
Chen, Jingyu
Moore, Andrew
Mangolini, Maurizio
Santoro, Antonella
Boyd, Joseph R
Schjerven, Hilde
Ecker, Veronika
Buchner, Maike
Williamson, James C
Lehner, Paul J
Gasparoli, Luca
Williams, Owen
Bloehdorn, Johannes
Stilgenbauer, Stephan
Leitges, Michael
Egle, Alexander
Schmidt-Supprian, Marc
Frietze, Seth
Ringshausen, Ingo
description Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell-autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)-β-dependent signals from bone marrow-derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal-regulated kinase (ERK)-mediated stabilization of B cell lymphoma-extra large (BCL-X ) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-β-dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-β, enhance the effectiveness of many antileukemic therapies.
doi_str_mv 10.1126/scitranslmed.aax9340
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identifier ISSN: 1946-6234
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subjects Apoptosis - drug effects
B-cell lymphoma
Bcl-x protein
Bone marrow
Chemotherapy
Cytotoxicity
Drug resistance
Drug Resistance, Neoplasm - genetics
Extracellular signal-regulated kinase
Humans
Lymphocytes B
Phosphorylation - drug effects
Protein kinase C
Protein Kinase C beta - metabolism
Signal transduction
Signal Transduction - genetics
Signal Transduction - physiology
Stromal cells
Stromal Cells - drug effects
Stromal Cells - metabolism
Transcription activation
Tumor cells
Tumor Cells, Cultured
title Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance
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