Abstract
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.
Highlights
Ovarian cancer is the deadliest malignancy among gynecological tumors and ranks 7th among the most frequently diagnosed carcinomas in women [1,2]
W1 ovarian cancer cell line and its cisplatin-resistant subtype W1CR, which is indicated by roughly a seven-fold higher EC50 value against cisplatin cytotoxicity, further increase resistance against cisplatin more than two-fold when they were cultivated on collagen type 1 (COL1) [9]
We show that cell adhesion-mediated drug resistance (CAM-DR) in W1 cells binding to COL1 is strictly dependent on ITGB1 activity following a p-PRAS/mechanistic target of rapamycin (mTOR) pathway, confirmed by a knockdown approach of this integrin
Summary
Ovarian cancer is the deadliest malignancy among gynecological tumors and ranks 7th among the most frequently diagnosed carcinomas in women [1,2]. The high mortality is on the one hand based on the late diagnosis of this malignancy, since symptoms often appear after the tumor has formed metastases. Resistance formation against these cytotoxic drugs appears another obstacle in treatment. The majority of patients initially respond well to these antineoplastic drugs, ovarian cancer has a high recurrence rate, which often goes along with resistance formation. A change in drug regime, including liposomal doxorubicin, topotecan, or gemcitabine cannot overcome resistance phenomena. This impressively illustrates the versatility of resistance mechanisms, ranging from mutational hyper-activation of proliferation signaling to changes in drug trafficking and metabolism to circumvent apoptosis. The relative 5-year survival rate of just 41% is comparably low [5]
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