Abstract | BACKGROUND: METHODS/PRINCIPAL FINDINGS: We found elevated profilin 1 (PFN) in human breast cancer tissues when compared to adjacent normal tissues. Overexpression of wild-type profilin 1 (PFN-WT) in breast cancer MCF7 cells made them more migratory, invasive and adherent independent in comparison to empty vector transfected cells. Mutation in serine phosphorylation site (S137) of profilin 1 (PFN-S137A) significantly abrogated these properties. Mutation affecting actin-binding ability (PFN-R74E) of profilin 1 enhanced its tumorigenic function whereas mutation affecting its poly-L-proline binding function (PFN-H133S) alleviated these mechanisms in breast cancer cells. PFN-WT was found to activate matrix metalloproteinases by zymography, MMP2 and MMP9 in presence of PDBu ( phorbol 12, 13 dibutyrate, PI3K agonist) to enhance migration and invasion in MCF7 cells while PFN-S137A did not. Phosphorylation increased migration and invasion in other mutants of profilin 1. Nuclear profilin levels also increased in the presence of PDBu. CONCLUSIONS: Previous studies show that profilin could be executing a dual role in cancer by either suppressing or promoting tumorigenesis in a context dependent manner. In this study we demonstrate for the first time that phosphorylation of profilin 1 at serine 137 enhances oncogenic properties in breast cancer cells. Inhibitors targeting profilin 1 phosphorylation directly or indirectly through inhibition of kinases that phosphorylate profilin could be valuable therapeutic agents that can alter its activity and thereby control the progression of cancer.
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Authors | Wasia Rizwani, Aneesa Fasim, Deepshikha Sharma, Divya J Reddy, Nabil A M Bin Omar, Surya S Singh |
Journal | PloS one
(PLoS One)
Vol. 9
Issue 8
Pg. e103868
( 2014)
ISSN: 1932-6203 [Electronic] United States |
PMID | 25084196
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- PFN1 protein, human
- Profilins
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Topics |
- Blotting, Western
- Breast Neoplasms
(genetics, metabolism)
- Cell Line, Tumor
- Electrophoresis, Polyacrylamide Gel
- Female
- Flow Cytometry
- Humans
- In Vitro Techniques
- Phosphorylation
(genetics, physiology)
- Profilins
(genetics, metabolism)
- Wound Healing
(genetics, physiology)
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