Introduction/Background DUSP6 is a negative regulator of the ERK signaling pathway. Previously we showed that DUSP6 is overexpressed in ovarian cancer side population(SP) cells that are quiescent and chemotherapy-resistant. Here, we explore the effects of DUSP6 on chemotherapy-resistance by examining its regulation of the ERK signaling pathway and G0/G1 cell cycle arrest.
Methodology mRNA and protein expression of DUSP6 and G0/G1 cell cycle checkpoint regulating proteins was evaluated among ovarian cancer cell lines and tissue samples. Ovarian cancer cells were transiently transfected to overexpress DUSP6. After treatment with cisplatin, cell viability was measured by the MTS assay at 48 hours and the half maximal inhibitory concentration(IC50) was calculated. Subcellular localization and cell cycle analysis were determined by using immunofluorescence and FACS.
Results SKOV3 and OVCAR8 SP cells expressed higher levels of DUSP6 and lower levels of CyclinD3 compared with non-SP(NSP) cells(P<0.001). Among 39 ovarian cancer tissue samples, expression of DUSP6 in the chemotherapy-resistant group(12 samples) was higher than in the chemotherapy-sensitive group(27 samples) (P<0.05). While a lower level of expression of CyclinD3 was seen in the chemotherapy-resistant group, it was not statistically different from the chemotherapy-sensitive group. HO8910 cells where shown to have higher IC50 to cisplatin than SKOV3 or OVCAR8 cells, and this correlated with higher levels of DUSP6 expression. Overexpression of DUSP6 in SKOV3 cells led to an increase in cisplatin IC50 values(P< 0.05), and also markedly reduced the expression levels of phospho-ERK1/2 and CyclinD3 and to the predominance of cells in the G0/G1 phase.
Conclusion Our findings reveal an enhancement of chemotherapy-resistance and a predominance of cells in G1 cell cycle arrest in DUSP6-overexpressing ovarian cancer cells. This suggests that overexpression of DUSP6 promotes chemotherapy-resistance through negative regulation of ERK signaling pathway, increasing the G0/G1 phase ratio among ovarian cancer cells, and leading to cellular quiescence.
Disclosure Nothing to disclose.
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