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IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer.
- Source :
-
RNA biology [RNA Biol] 2021 Mar; Vol. 18 (3), pp. 391-403. Date of Electronic Publication: 2020 Sep 02. - Publication Year :
- 2021
-
Abstract
- Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HGSOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here, we show that the IGF2 mRNA-binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HGSOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in an RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signalling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation, only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rationale for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HGSOC.
- Subjects :
- Adherens Junctions genetics
Adherens Junctions metabolism
Animals
Biomarkers, Tumor
Cell Line, Tumor
Disease Models, Animal
Epithelial-Mesenchymal Transition genetics
Female
Humans
Mice
Mitogen-Activated Protein Kinases antagonists & inhibitors
Ovarian Neoplasms drug therapy
Ovarian Neoplasms pathology
Protein Binding
Protein Interaction Domains and Motifs
Protein Kinase Inhibitors pharmacology
RNA-Binding Proteins metabolism
Xenograft Model Antitumor Assays
src Homology Domains
src-Family Kinases antagonists & inhibitors
Gene Expression Regulation, Neoplastic
Mitogen-Activated Protein Kinases metabolism
Ovarian Neoplasms etiology
Ovarian Neoplasms metabolism
RNA-Binding Proteins genetics
Signal Transduction drug effects
src-Family Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1555-8584
- Volume :
- 18
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- RNA biology
- Publication Type :
- Academic Journal
- Accession number :
- 32876513
- Full Text :
- https://doi.org/10.1080/15476286.2020.1812894