Cisplatin-induced ERK1/2 activity promotes G1 to S phase progression which leads to chemoresistance of ovarian cancer cells

Abstract

The link between ERK1/2 activity and cisplatin cytotoxicity, in association with the cell cycle, in ovarian cancer cell lines resistant (A2780cis; SK-OV-3) and sensitive (A2780) to cisplatin was determined. We observed that cisplatin, at a low concentration enhanced the activation of ERK1/2 in A2780 cells and increased their accumulation in the S phase, resulting in low cytotoxicity. A high concentration of drug induced dephosphorylation and degradation of ERK1/2 and was extremely toxic, accumulating most of to these cells in the sub-G1 phase. The PD98059, pharmacological inhibitor of ERK1/2 activation, increased the cytotoxicity of cisplatin applied at a low concentration to A2780 cells (decreased ERK1/2 activity), causing shift of cell accumulation from the S to G1 phase. Surprisingly, PD98059 enhanced cell viability when a chemotherapeutic was used at high concentration, intensifying phosphorylation level of ERK1/2 and reversing cell cycle arrest in sub-G1 to promote the G1 and S phases. A2780cis cells demonstrated resistance to cisplatin with high ERK1/2 activity and accumulation of cells in the G1 and S phases. PD98059 sensitized resistant cells to drug toxicity during the first 24 hours of treatment, with blocked ERK1/2 phosphorylation and prevented progression from the G1 to S phase. SK-OV-3 resistant cells characterized with extremely high basal phosphorylation of ERK1/2, which wasn't changed after exposure to cisplatin. Administration of PD98059 didn't change the cytotoxicity of cisplatin in these cells. In conclusion, ERK1/2, activated by cisplatin, participates in the cell cycle progression from the G1 to S phase, enhancing cells’ survival and drug resistance.

Gemcitabine‐induced epithelial‐mesenchymal transition‐like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal‐like phenotype

“…Also, no potential interest was found for ERK1/2 inhibition in the gemcitabine resistance of pancreatic tumor cell lines of epithelial phenotype. Interestingly, similar observations were recently reported for the resistance to cisplatin of ovarian cancer cells . Although inhibition of ERK1,2 sensitized cisplatin‐resistant ovarian cells to cisplatin, treatment of parental ovarian cells by 25μM cisplatin combined with ERK inhibition resulted in enhanced cell viability in comparison to cisplatin alone.…”

Predicting response to platinum and non-platinum drugs through bioluminescence resonance energy transfer (BRET) based bio-molecular interactions in platinum resistant epithelial ovarian cancer

“…Re-challenging platinum-taxol resistant Dual LR cells and intrinsically platinum-resistant SKOV3 cells with cisplatin-paclitaxel specifically increased NEO BRET ratio and ERK1/2 phosphorylation without any significant alteration in the NAT-BRET ratio or AKT phosphorylation, implying prominent role of ERK1/2 mediated signaling in platinum-taxol induced therapeutic stress. Such trend was also reported by multiple studies encompassing hepatocellular as well as ovarian carcinoma [ 35 , 36 ]. However, both ERK1/2 and AKT activations were captured by NEO & NAT-BRET systems and by western blots in malignant ascites derived cancel cells from platinum resistant HGSOC patients.…”

The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma

“…Activation of MEK1/2 pathway was previously reported in some HGSOC cells in response to high doses of cisplatin and may be linked to development of cisplatin resistance [ 39 , 40 , 47 , 48 ]. We therefore used OVCAR8 and PEO4 cell lines (displaying moderate pMEK1/2 levels, Figure 2 C) to confirm that these effects are reproduced in our model systems.…”