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Article

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

1
Department of Pharmacy, University of Bonn, 53113 Bonn, Germany
2
Department of RNA Metabolism, Institute of Bioorganic Chemistry Polish Academy of Sciences, 61-704 Poznań, Poland
3
Institute of Health Sciences, Collegium Medicum, University of Zielona Gora, Zyty 28 St., 65-046 Zielona Góra, Poland
*
Author to whom correspondence should be addressed.
Authors equally contributed.
Int. J. Mol. Sci. 2020, 21(23), 9240; https://doi.org/10.3390/ijms21239240
Received: 13 November 2020 / Revised: 1 December 2020 / Accepted: 1 December 2020 / Published: 3 December 2020
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment)
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. View Full-Text
Keywords: CAM-DR; cisplatin; collagen; ovarian cancer; chemoresistance; HSP27 CAM-DR; cisplatin; collagen; ovarian cancer; chemoresistance; HSP27
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MDPI and ACS Style

Wantoch von Rekowski, K.; König, P.; Henze, S.; Schlesinger, M.; Zawierucha, P.; Januchowski, R.; Bendas, G. Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies. Int. J. Mol. Sci. 2020, 21, 9240. https://doi.org/10.3390/ijms21239240

AMA Style

Wantoch von Rekowski K, König P, Henze S, Schlesinger M, Zawierucha P, Januchowski R, Bendas G. Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies. International Journal of Molecular Sciences. 2020; 21(23):9240. https://doi.org/10.3390/ijms21239240

Chicago/Turabian Style

Wantoch von Rekowski, Kathleen, Philipp König, Svenja Henze, Martin Schlesinger, Piotr Zawierucha, Radosław Januchowski, and Gerd Bendas. 2020. "Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies" International Journal of Molecular Sciences 21, no. 23: 9240. https://doi.org/10.3390/ijms21239240

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