Cisplatin-induced ERK1/2 activity promotes G1 to S phase progression which leads to chemoresistance of ovarian cancer cells
Metrics: PDF 1680 views | HTML 2012 views | ?
Michal Kielbik1, Damian Krzyzanowski1, Bartlomiej Pawlik1,2 and Magdalena Klink1
1Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
2Institute of Microbiology, Biotechnology and Immunology, University of Lodz, Lodz, Poland
Magdalena Klink, email: [email protected]
Keywords: ovarian cancer cells; cisplatin resistance; ERK1/2 signaling pathway; cell cycle; MEK1/2 inhibitor
Received: July 26, 2017 Accepted: March 06, 2018 Published: April 13, 2018
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.