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

International Journal of Molecular Sciences

Svenja Henze¹  KathleenWantoch von Rekowski¹  Martin Schlesinger¹  Gerd Bendas¹  Philipp König¹  Piotr Zawierucha²  Radosław Januchowski³ 

[1] Department of Pharmacy, University of Bonn, 53113 Bonn, Germany;Department of RNA Metabolism, Institute of Bioorganic Chemistry Polish Academy of Sciences, 61-704 Poznań, Poland;Institute of Health Sciences, Collegium Medicum, University of Zielona Gora, Zyty 28 St., 65-046 Zielona Góra, Poland;

关键词: CAM-DR;    cisplatin;    collagen;    ovarian cancer;    chemoresistance;    HSP27;   

DOI  :  10.3390/ijms21239240

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown