title: Alterative Expression and Localization of Profilin 1/VASPpS157 and Cofilin 1/VASPpS239 Regulates Metastatic Growth and Is Modified by DHA Supplementation.
abstract: Profilin 1, cofilin 1, and vasodialator-stimulated phosphoprotein (VASP) are actin-binding proteins (ABP) that regulate actin remodeling and facilitate cancer cell metastases. miR-17-92 is highly expressed in metastatic tumors and profilin1 and cofilin1 are predicted targets. Docosahexaenoic acid (DHA) inhibits cancer cell proliferation and adhesion. These studies tested the hypothesis that the metastatic phenotype is driven by changes in ABPs including alternative phosphorylation and/or changes in subcellular localization. In addition, we tested the efficacy of DHA supplementation to attenuate or inhibit these changes. Human lung cancer tissue sections were analyzed for F-actin content and expression and cellular localization of profilin1, cofilin1, and VASP (S157 or S239 phosphorylation). The metastatic phenotype was investigated in A549 and MLE12 cells lines using 8 Br-cAMP as a metastasis inducer and DHA as a therapeutic agent. Migration was assessed by wound assay and expression measured by Western blot and confocal analysis. miR-17-92 expression was measured by qRT-PCR. Results indicated increased expression and altered cellular distribution of profilin1/VASP(pS157), but no changes in cofilin1/VASP(pS239) in the human malignant tissues compared with normal tissues. In A549 and MLE12 cells, the expression patterns of profilin1/VASP(pS157) or cofilin1/VASP(pS239) suggested an interaction in regulation of actin dynamics. Furthermore, DHA inhibited cancer cell migration and viability, ABP expression and cellular localization, and modulated expression of miR-17-92 in A549 cells with minimal effects in MLE12 cells. Further investigations are warranted to understand ABP interactions, changes in cellular localization, regulation by miR-17-92, and DHA as a novel therapeutic. Mol Cancer Ther; 15(9); 2220-31. ©2016 AACR.
authors: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio. mehboob.ali@nationwidechildrens.org.
authors: Mehboob
authors: M
authors: Ali
authors: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors: Kathryn
authors: K
authors: Heyob
authors: Department of Radiation Oncology, The Ohio State University, Columbus, Ohio.
authors: Naduparambil K
authors: NK
authors: Jacob
authors: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio. Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors: Lynette K
authors: LK
authors: Rogers
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D051338:Cofilin 1 / Q000235:genetics* / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000008:administration & dosage; D019587:Dietary Supplements; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051304:Profilins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D051338:Cofilin 1; C524941:MIRN17 microRNA, human; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; D010750:Phosphoproteins; D051304:Profilins; D000098662:Vasodilator-Stimulated Phosphoprotein; D003687:Dehydroepiandrosterone; D000242:Cyclic AMP