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. 2020 Aug;20(2):1743-1751.
doi: 10.3892/ol.2020.11741. Epub 2020 Jun 16.

MKP-1 overexpression is associated with chemoresistance in bladder cancer via the MAPK pathway

Siyu Lei  1   2 , Hong Xu  1   2 , Naiwen Chen  1   2 , Huan Pan  3 , Wenhua Xie  1 , Yi He  1 , Jing Jin  1
Affiliations

MKP-1 overexpression is associated with chemoresistance in bladder cancer via the MAPK pathway

Siyu Lei et al. Oncol Lett. 2020 Aug.

Abstract

Mitogen activated protein kinase phosphatase-1 (MKP-1) has been revealed to be overexpressed in bladder cancer, particularly in non-muscle invasive bladder cancer. MKP-1 may also be associated with chemotherapy resistance. However, the underlying mechanism is yet to be elucidated. The current study investigated the expression of MKP-1 by performing immunohistochemistry in surgically resected specimens obtained from primary and recurrent patients with bladder cancer. The results revealed that MKP-1 expression increased in recurrent patients. Additionally, a 3D model of the human bladder cancer cell line, RT112, was established to determine the role of MKP-1 in drug resistance. The results demonstrated that MKP-1 overexpression protected bladder cancer cells against cell death. Contrarily, MKP-1 knockdown was revealed to sensitize cells to death. In addition, the application of MAPK inhibitors effectively increased RT112 cell sensitivity to pirarubicin. In conclusion, the results of the current study indicated that MKP-1 treatment resulted in bladder cancer cell chemoresistance via JNK, ERK and p38 pathways. MKP-1 may also serve as a potential therapeutic target for chemoresistance in patients with bladder cancer.

Keywords: 3D model; RT112 cell; bladder cancer; fibroblast growth factor 3; mitogen activated protein kinase phosphatase-1; resistance.

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Figures

Figure 1.
Figure 1.
FGFR3 and MKP-1 expression levels are increased in recurrent bladder cancer tissue. (A) Immunohistochemical staining of primary and recurrent bladder cancer tissues was performed to detect FGFR3 and MKP-1 expression in representative patients. Scale bar, 100 µm. (B) Quantitative FGFR3 expression was analyzed using the Image-pro Plus 6.0 system. Histograms represent the mean density of FGFR3. (C) Quantitative MKP-1 expression was analyzed using the Image-pro Plus 6.0 system. Histograms represent the mean density of MKP-1. (D) Relative MKP-1 expression was determined by reverse transcription-quantitative PCR. *P<0.05. FGFR3, fibroblast growth factor receptor 3; MKP-1, mitogen activated protein kinase phosphatase-1; IHC, immunohistochemistry.
Figure 2.
Figure 2.
MKP-1 and MAPK expression in RT112 cells transfected with NC and MKP-1 siRNA. (A) Relative MKP-1 expression in the siNC and siMKP-1 groups was examined using reverse transcription-quantitative PCR. **P<0.01. (B) Representative microscopic images of siNC and siMKP-1 treated cells captured in both 2D and 3D environments under a phase contrast microscope. (C) MKP-1 expression of the siNC and siMKP-1 groups, as determined via western blotting. GAPDH was used as the internal control. (D) Phosphorylated and total ERK1/2 protein expressions of the siNC and siMKP-1 group, as determined via western blotting. GAPDH was used as the internal control. (E) Phosphorylated and total p38 protein expressions of the siNC and siMKP-1 group, as determined via western blotting. GAPDH was used as the internal control. (F) Phosphorylated and total JNK protein expression levels of the siNC and siMKP-1 group, as determined via western blotting. GAPDH was used as the internal control. MKP-1, mitogen activated protein kinase phosphatase-1; NC, negative control; siMKP-1, MKP-1 small interfering RNA; siNC, small interfering negative control.
Figure 3.
Figure 3.
MKP-1 knockdown increases drug-susceptibility and induces cell apoptosis. Dose responses and the timed course of cell death in siNC and siMKP-1 treated cells is presented. (A) Two groups of cells were treated with increasing concentrations (0, 5, 10, 20, 40, 80, 160 and 320 nmol/l) of THP for 24 h. (B) Two groups of cells were treated with 80 nmol/l THP and incubated for different durations (24, 48 and 72 h). Cell viability was determined via Cell Counting Kit-8 assays. *P<0.05 and **P<0.01. (C) Cell apoptosis of the two groups was measured via flow cytometry with or without 80 nmol/l THP treatment. (D) A comparison of apoptosis rates between the two groups is presented. **P<0.01. MKP-1, mitogen activated protein kinase phosphatase-1; siNC, small interfering negative control; siMKP-1, MKP-1 small interfering RNA; THP, pirarubicin.
Figure 4.
Figure 4.
Effect of MAPK inhibitors on cell death. (A) siNC and siMKP-1 groups were left untreated or pretreated with SP600125, PD98059 and SB202190. Subsequently, samples were treated with 80 nmol/l THP. Cell viability was determined via Cell Counting Kit-8 assays. *P<0.05 and **P<0.01. (B) Levels of phosphorylated and total JNK protein were determined via western blotting. Actin was used as the internal control. (C) Levels of phosphorylated and total p38 protein were determined via western blotting. Actin was used as the internal control. (D) Levels of phosphorylated and total ERK1/2 protein were determined via western blotting. Actin was used as the internal control. siNC, small interfering negative control; siMKP-1, MKP-1 small interfering RNA; THP, pirarubicin.
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