Abstract | BACKGROUND: METHODS: RESULTS: We here show that stable knockdown of flotillin-1 in MCF7 cells resulted in upregulation of EGFR mRNA and protein expression and hyperactivation of MAPK signaling, whereas ErbB2 and ErbB3 expression were not affected. Treatment of the flotillin knockdown cells with an EGFR inhibitor reduced the MAPK signaling, demonstrating that the increased EGFR expression and activity is the cause of the increased signaling. Stable ectopic expression of flotillins in the knockdown cells reduced the increased EGFR expression, demonstrating a direct causal relationship between flotillin-1 expression and EGFR amount. Furthermore, the upregulation of EGFR was dependent on the PI3K signaling pathway which is constitutively active in MCF7 cells, and PI3K inhibition resulted in reduced EGFR expression. CONCLUSIONS: This study demonstrates that flotillins may not be suitable as cancer therapy targets in cells that carry certain other oncogenic mutations such as PI3K activating mutations, as unexpected effects are prone to emerge upon flotillin knockdown which may even facilitate cancer cell growth and proliferation.
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Authors | Nina Kurrle, Wymke Ockenga, Melanie Meister, Frauke Völlner, Sina Kühne, Bincy A John, Antje Banning, Ritva Tikkanen |
Journal | BMC cancer
(BMC Cancer)
Vol. 13
Pg. 575
(Dec 05 2013)
ISSN: 1471-2407 [Electronic] England |
PMID | 24304721
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chromones
- Membrane Proteins
- Morpholines
- Phosphoinositide-3 Kinase Inhibitors
- flotillins
- 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
- Epidermal Growth Factor
- EGFR protein, human
- ErbB Receptors
- Mitogen-Activated Protein Kinases
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Topics |
- Breast Neoplasms
- Cell Proliferation
- Chromones
(pharmacology)
- Endocytosis
- Epidermal Growth Factor
(physiology)
- ErbB Receptors
(genetics, metabolism)
- Female
- Gene Expression
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Humans
- MAP Kinase Signaling System
- MCF-7 Cells
- Membrane Proteins
(genetics, metabolism)
- Mitogen-Activated Protein Kinases
(metabolism)
- Morpholines
(pharmacology)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Phosphoinositide-3 Kinase Inhibitors
- Protein Transport
- Up-Regulation
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