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Downregulation of MACC1 expression enhances cisplatin sensitivity in SKOV-3/DDP cells
1First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Abstract:
The aim of this study was to investigate the correlation between MACC1 expression and resistance to cisplatin (DDP) in DDP-resistant human epithelial ovarian cancer SKOV-3 cells (SKOV-3/DDP). MACC1 mRNA and protein expression levels in SKOV-3 and SKOV-3/DDP cells were detected by reverse transcriptase polymerase chain reaction and western blot. The SKOV-3/DDP cells were divided into 5 groups: control, shVect (transfected with p-super-EGFP-1 plasmid), pshMACC1 (transfected with psuper-EGFP-shMACC1 plasmid), PD (pretreated with 20 μM PD98059), and combined (transfected with psuper-EGFP-shMACC1 plasmid and pretreated with 20 μM PD98059) groups. Cisplatin sensitivity and cell apoptosis in SKOV-3/DDP cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. ERK1/2 and p-ERK1/2 expression was determined by western blot. MACC1 mRNA and protein expression levels in SKOV-3/DDP cells were 2.66 ± 0.54 and 1.95 ± 0.45 times those seen in SKOV-3 cells (P < 0.05). Cisplatin sensitivity of pshMACC1 group was much higher than that in the control and shVect groups. Cisplatin-induced cell apoptosis rates increased significantly in the pshMACC1, PD, and combined groups, compared to the control and shVect groups. Moreover, the apoptosis rate was the highest in the combined group among the 5 groups (IC50 = 20.836 ± 0.629 μM). p-ERK1/2 expression decreased significantly in the pshMACC1, PD, and combined groups (this decrease was the most obvious in the combined group). In conclusion, downregulation of MACC1 expression could enhance cisplatin sensitivity and decrease drug resistance in SKOV- 3/DDP cells.
Insights
Downregulating MACC1 expression enhances cisplatin sensitivity and reduces drug resistance in ovarian cancer cells. This involves inhibiting the ERK1/2 pathway, leading to increased apoptosis and improved treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cisplatin (DDP) resistance is a major challenge in epithelial ovarian cancer treatment.
- Metastasis Associated In Cancer 1 (MACC1) has been implicated in various cancers, but its role in DDP resistance is not fully understood.
Purpose of the Study:
- To investigate the correlation between MACC1 expression and cisplatin resistance in DDP-resistant human epithelial ovarian cancer SKOV-3 cells (SKOV-3/DDP).
- To explore the effect of MACC1 downregulation on cisplatin sensitivity, apoptosis, and the ERK1/2 signaling pathway in SKOV-3/DDP cells.
Main Methods:
- MACC1 mRNA and protein expression were quantified using RT-PCR and Western blot.
- SKOV-3/DDP cells were treated with MACC1 shRNA (pshMACC1) and/or PD98059 (an ERK1/2 inhibitor).
- Cisplatin sensitivity (IC50) and apoptosis rates were assessed via MTT assay and flow cytometry, respectively. ERK1/2 and p-ERK1/2 levels were analyzed by Western blot.
Main Results:
- MACC1 expression was significantly higher in SKOV-3/DDP cells compared to SKOV-3 cells.
- Downregulation of MACC1 (pshMACC1) significantly increased cisplatin sensitivity and apoptosis rates.
- Combined MACC1 downregulation and PD98059 treatment resulted in the highest apoptosis rate and significantly reduced p-ERK1/2 expression.
Conclusions:
- MACC1 expression is positively correlated with cisplatin resistance in ovarian cancer cells.
- Downregulating MACC1 enhances cisplatin sensitivity and induces apoptosis, partly through the inhibition of the ERK1/2 pathway.
- Targeting MACC1 and the ERK1/2 pathway represents a potential therapeutic strategy to overcome cisplatin resistance in ovarian cancer.
