Non-phosphorylatable PEA-15 sensitises SKOV-3 ovarian cancer cells to cisplatin

  • 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 2-related 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.

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Author:Shahana Dilruba, Alessia GrondanaORCiD, Anke C. SchiedelORCiDGND, Naoto T. Ueno, Chandra Bartholomeusz, Jindrich CinatlORCiDGND, Katie-May McLaughlin, Mark N. WassORCiD, Martin MichaelisORCiDGND, Ganna V. Kalayda
URN:urn:nbn:de:hebis:30:3-544244
DOI:https://doi.org/10.3390/cells9020515
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/32102425
Parent Title (English):Cells
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Date of Publication (online):2020/02/24
Date of first Publication:2020/02/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/04/09
Tag:PEA-15; cisplatin sensitivity; ovarian cancer
Volume:9
Issue:515
Page Number:17
Note:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
HeBIS-PPN:463772261
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0