Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies

The microenvironment possesses a strong impact on the tumor chemoresistance when cells bind to components of the extracellular matrix. Here we elucidate the signaling pathways of cisplatin resistance in W1 ovarian cancer cells binding to collagen type 1 (COL1) and signaling interference with constit...

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Main Authors: Kathleen Wantoch von Rekowski, Philipp König, Svenja Henze, Martin Schlesinger, Piotr Zawierucha, Radosław Januchowski, Gerd Bendas
Format: Article
Language:English
Published: MDPI AG 2020-12-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/21/23/9240
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author Kathleen Wantoch von Rekowski
Philipp König
Svenja Henze
Martin Schlesinger
Piotr Zawierucha
Radosław Januchowski
Gerd Bendas
author_facet Kathleen Wantoch von Rekowski
Philipp König
Svenja Henze
Martin Schlesinger
Piotr Zawierucha
Radosław Januchowski
Gerd Bendas
author_sort Kathleen Wantoch von Rekowski
collection DOAJ
description The microenvironment possesses a strong impact on the tumor chemoresistance when cells bind to components of the extracellular matrix. Here we elucidate the signaling pathways of cisplatin resistance in W1 ovarian cancer cells binding to collagen type 1 (COL1) and signaling interference with constitutive cisplatin resistance in W1CR cells to discover the targets for sensitization. Proteome kinase arrays and Western blots were used to identify the signaling components, their impact on cisplatin resistance was evaluated by inhibitory or knockdown approaches. W1 cell binding to COL1 upregulates integrin-associated signals via FAK/PRAS40/mTOR, confirmed by β1-integrin (ITGB1) knockdown. mTOR appears as key for resistance, its blockade reversed COL1 effects on W1 cell resistance completely. W1CR cells compensate ITGB1-knockdown by upregulation of discoidin domain receptor 1 (DDR1) as alternative COL1 sensor. COL1 binding via DDR1 activates the MAPK pathway, of which JNK1/2 appears critical for COL1-mediated resistance. JNK1/2 inhibition inverts COL1 effects in W1CR cells, whereas intrinsic cisplatin resistance remained unaffected. Remarkably, knockdown of HSP27, another downstream MAPK pathway component overcomes intrinsic resistance completely sensitizing W1CR cells to the level of W1 cells for cisplatin cytotoxicity. Our data confirm the independent regulation of matrix-induced and intrinsic chemoresistance in W1 ovarian cancer cells and offer novel targets for sensitization.
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spelling doaj.art-cdd4d695ccc5447f98ac21ee069b0a7f2023-11-20T23:26:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012123924010.3390/ijms21239240Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization StrategiesKathleen Wantoch von Rekowski0Philipp König1Svenja Henze2Martin Schlesinger3Piotr Zawierucha4Radosław Januchowski5Gerd Bendas6Department of Pharmacy, University of Bonn, 53113 Bonn, GermanyDepartment of Pharmacy, University of Bonn, 53113 Bonn, GermanyDepartment of Pharmacy, University of Bonn, 53113 Bonn, GermanyDepartment of Pharmacy, University of Bonn, 53113 Bonn, GermanyDepartment of RNA Metabolism, Institute of Bioorganic Chemistry Polish Academy of Sciences, 61-704 Poznań, PolandInstitute of Health Sciences, Collegium Medicum, University of Zielona Gora, Zyty 28 St., 65-046 Zielona Góra, PolandDepartment of Pharmacy, University of Bonn, 53113 Bonn, GermanyThe microenvironment possesses a strong impact on the tumor chemoresistance when cells bind to components of the extracellular matrix. Here we elucidate the signaling pathways of cisplatin resistance in W1 ovarian cancer cells binding to collagen type 1 (COL1) and signaling interference with constitutive cisplatin resistance in W1CR cells to discover the targets for sensitization. Proteome kinase arrays and Western blots were used to identify the signaling components, their impact on cisplatin resistance was evaluated by inhibitory or knockdown approaches. W1 cell binding to COL1 upregulates integrin-associated signals via FAK/PRAS40/mTOR, confirmed by β1-integrin (ITGB1) knockdown. mTOR appears as key for resistance, its blockade reversed COL1 effects on W1 cell resistance completely. W1CR cells compensate ITGB1-knockdown by upregulation of discoidin domain receptor 1 (DDR1) as alternative COL1 sensor. COL1 binding via DDR1 activates the MAPK pathway, of which JNK1/2 appears critical for COL1-mediated resistance. JNK1/2 inhibition inverts COL1 effects in W1CR cells, whereas intrinsic cisplatin resistance remained unaffected. Remarkably, knockdown of HSP27, another downstream MAPK pathway component overcomes intrinsic resistance completely sensitizing W1CR cells to the level of W1 cells for cisplatin cytotoxicity. Our data confirm the independent regulation of matrix-induced and intrinsic chemoresistance in W1 ovarian cancer cells and offer novel targets for sensitization.https://www.mdpi.com/1422-0067/21/23/9240CAM-DRcisplatincollagenovarian cancerchemoresistanceHSP27
spellingShingle Kathleen Wantoch von Rekowski
Philipp König
Svenja Henze
Martin Schlesinger
Piotr Zawierucha
Radosław Januchowski
Gerd Bendas
Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies
International Journal of Molecular Sciences
CAM-DR
cisplatin
collagen
ovarian cancer
chemoresistance
HSP27
title Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies
title_full Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies
title_fullStr Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies
title_full_unstemmed Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies
title_short Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies
title_sort insight into cisplatin resistance signaling of w1 ovarian cancer cells emerges mtor and hsp27 as targets for sensitization strategies
topic CAM-DR
cisplatin
collagen
ovarian cancer
chemoresistance
HSP27
url https://www.mdpi.com/1422-0067/21/23/9240
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