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Non-Phosphorylatable PEA-15 Sensitises SKOV-3 Ovarian Cancer Cells to Cisplatin
Shahana Dilruba1, Alessia Grondana1, Anke C Schiedel2
1Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, 53113 Bonn, Germany.
Abstract:
The efficacy of cisplatin-based chemotherapy in ovarian cancer is often limited by the development of drug resistance. In most ovarian cancer cells, cisplatin activates extracellular signal-regulated kinase1/2 (ERK1/2) signalling. Phosphoprotein enriched in astrocytes (PEA-15) is a ubiquitously expressed protein, capable of sequestering ERK1/2 in the cytoplasm and inhibiting cell proliferation. This and other functions of PEA-15 are regulated by its phosphorylation status. In this study, the relevance of PEA-15 phosphorylation state for cisplatin sensitivity of ovarian carcinoma cells was examined. The results of MTT-assays indicated that overexpression of PEA-15AA (a non-phosphorylatable variant) sensitised SKOV-3 cells to cisplatin. Phosphomimetic PEA-15DD did not affect cell sensitivity to the drug. While PEA-15DD facilitates nuclear translocation of activated ERK1/2, PEA-15AA acts to sequester the kinase in the cytoplasm as shown by Western blot. Microarray data indicated deregulation of thirteen genes in PEA-15AA-transfected cells compared to non-transfected or PEA-15DD-transfected variants. Data derived from The Cancer Genome Atlas (TCGA) showed that the expression of seven of these genes including EGR1 (early growth response protein 1) and FLNA (filamin A) significantly correlated with the therapy outcome in cisplatin-treated cancer patients. Further analysis indicated the relevance of nuclear factor erythroid 2related factor 2/antioxidant response element (Nrf2/ARE) signalling for the favourable effect of PEA-15AA on cisplatin sensitivity. The results warrant further evaluation of the PEA-15 phosphorylation status as a potential candidate biomarker of response to cisplatin-based chemotherapy.
Insights
Altering the phosphorylation of Phosphoprotein enriched in astrocytes (PEA-15) can sensitize ovarian cancer cells to cisplatin chemotherapy. This suggests PEA-15
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cisplatin resistance limits ovarian cancer chemotherapy efficacy.
- Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling is activated by cisplatin in ovarian cancer.
- Phosphoprotein enriched in astrocytes (PEA-15) regulates ERK1/2 localization and cellular functions based on its phosphorylation.
Purpose of the Study:
- To investigate the role of PEA-15 phosphorylation status in modulating cisplatin sensitivity in ovarian carcinoma cells.
- To determine if specific PEA-15 variants affect cellular response to cisplatin treatment.
Main Methods:
- MTT assays were used to assess cell viability and drug sensitivity.
- Western blot analysis was performed to examine ERK1/2 localization.
- Microarray analysis identified gene expression changes in PEA-15 transfected cells.
- The Cancer Genome Atlas (TCGA) data was analyzed for gene expression and patient outcome correlations.
Main Results:
- Overexpression of a non-phosphorylatable PEA-15 variant (PEA-15AA) sensitized SKOV-3 cells to cisplatin.
- A phosphomimetic PEA-15 variant (PEA-15DD) did not alter cisplatin sensitivity.
- PEA-15AA sequestered ERK1/2 in the cytoplasm, while PEA-15DD promoted its nuclear translocation.
- Deregulation of thirteen genes, including EGR1 and FLNA, was observed in PEA-15AA cells, with seven correlating with patient outcomes in TCGA data.
- Nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling was implicated in the favorable effect of PEA-15AA.
Conclusions:
- PEA-15 phosphorylation status influences ovarian cancer cell sensitivity to cisplatin.
- PEA-15AA enhances cisplatin sensitivity by cytoplasmic sequestration of ERK1/2 and modulation of specific gene expression.
- PEA-15 phosphorylation may serve as a predictive biomarker for response to cisplatin-based chemotherapy.
