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

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.

Heat Shock Protein 27, a Novel Downstream Target of Collagen Type XI alpha 1, Synergizes with Fatty Acid Oxidation to Confer Cisplatin Resistance in Ovarian Cancer Cells

“…Here we showed that COL11A1, and not type I collagen, upregulates total and phosphorylated HSP27 in ovarian cancer cells. Other research groups have shown that type I collagen can induce HSP27 phosphorylation in platelets [ 42 , 43 ] and the W1 ovarian cancer cell line [ 44 ]. Differences in these studies and our results could be explained by receptor expression in these cells.…”

Piperine Targets Different Drug Resistance Mechanisms in Human Ovarian Cancer Cell Lines Leading to Increased Sensitivity to Cytotoxic Drugs

“…The presence of CSCs [ 26 , 29 , 30 , 31 , 32 , 33 , 34 , 58 ], expression of drug transporters [ 11 , 13 , 31 , 58 ], and ECM molecules [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 27 , 28 ] are the most important mechanism of drug resistance. Increased expression of drug resistance genes seems to be associated with increased signal transduction that results from an imbalance between phosphorylation and dephosphorylation of tyrosine [ 35 , 36 , 37 , 38 , 39 , 40 , 59 ].…”

“…However, the expression of ECM components and CAM-DR seems not to be limited to cancer tissue. Recently, we [ 20 , 21 , 22 , 23 ] and others [ 24 ] observed the expression of different ECM components in drug-resistant cancer cell lines suggesting their active role in CAM-DR [ 25 , 26 ]. Notably, we observed a very high expression of COL3A1 in PAC and TOP-resistant cell lines suggesting the role of this protein in resistance to these drugs [ 27 , 28 ].…”

Overexpression of E74‑like transformation‑specific transcription factor 3 promotes cellular proliferation and predicts poor prognosis in ovarian cancer

“…The present study reported that ELF3 was upregulated in cisplatin-resistant OC cells, and that ELF3 reduced cisplatin sensitivity by inhibiting apoptosis. Notably, mTOR signaling (promoting cisplatin resistance) was reported in non-small cell lung cancer, OC and hepatocellular carcinoma (31)(32)(33), suggesting that ELF3 reduces cisplatin sensitivity through activation of the mTOR pathway. However, this speculation requires further experimental confirmation.…”