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Alterative Expression and Localization of Profilin 1/VASP and Cofilin 1

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Alterative Expression and Localization of Profilin 1/VASP and Cofilin 1 Published OnlineFirst August 5, 2016; DOI: 10.1158/1535-7163.MCT-16-0092 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics Alterative Expression and Localization of Profilin 1/VASPpS157 and Cofilin 1/VASPpS239 Regulates Metastatic Growth and Is Modified by DHA Supplementation Mehboob Ali1, Kathryn Heyob1, Naduparambil K. Jacob2, and Lynette K. Rogers1,3 Abstract Profilin 1, cofilin 1, and vasodialator-stimulated phosphopro- was assessed by wound assay and expression measured by tein (VASP) are actin-binding proteins (ABP) that regulate actin Western blot and confocal analysis. miR-17-92 expression was remodeling and facilitate cancer cell metastases. miR-17-92 is measured by qRT-PCR. Results indicated increased expression highly expressed in metastatic tumors and profilin1 and cofilin1 and altered cellular distribution of profilin1/VASPpS157,butno are predicted targets. Docosahexaenoic acid (DHA) inhibits can- changes in cofilin1/VASPpS239 in the human malignant tissues cer cell proliferation and adhesion. These studies tested the compared with normal tissues. In A549 and MLE12 cells, the hypothesis that the metastatic phenotype is driven by changes expression patterns of profilin1/VASPpS157 or cofilin1/VASPpS239 in ABPs including alternative phosphorylation and/or changes in suggested an interaction in regulation of actin dynamics. Fur- subcellular localization. In addition, we tested the efficacy of DHA thermore, DHA inhibited cancer cell migration and viability, supplementation to attenuate or inhibit these changes. Human ABP expression and cellular localization, and modulated expres- lung cancer tissue sections were analyzed for F-actin content and sion of miR-17-92 in A549 cells with minimal effects in MLE12 expression and cellular localization of profilin1, cofilin1, and cells. Further investigations are warranted to understand ABP VASP (S157 or S239 phosphorylation). The metastatic phenotype interactions, changes in cellular localization, regulation by miR- was investigated in A549 and MLE12 cells lines using 8 Br-cAMP as 17-92, and DHA as a novel therapeutic. Mol Cancer Ther; 15(9); a metastasis inducer and DHA as a therapeutic agent. Migration 2220–31. Ó2016 AACR. Introduction recurrent disease due to resistance to cell death (apoptosis) and permanent cell-cycle kinetics changes (1, 8, 11–13). Taken Metastasis to distant organs and persistent survival of cancer together, these considerations underscore the urgent need for cells reflect high disease cancer mortality rates (1–3). Overall, unraveling fundamental signaling mechanisms involved in statistics project a total of 1,665,540 new cases associated with cancer cell survival and metastasis that could be translated into cancer in the United States in 2014 (4). Although death rates novel therapeutics. declined 20% from 1991 to 2009, cancer still imposes an intol- The process of metastasis is facilitated by defects in actin erable socioeconomical toll (1,600 deaths/day; refs. 4–6). Unfor- dynamics that disrupt normal cell homeostasis promoting tunately, curative chemotherapeutic approaches have not changes in cell polarity, adhesion, and proliferation (14–17). emerged and current adjuvant chemotherapies are largely ineffi- Actin dynamics are also known to affect cancer cell survival where cient against cancer cells with the complete malignant phenotype, increased F-actin turnover promotes cell viability and decreased increasing median survival by only a few years and with a F-actin turnover inhibits it through apoptosis (18–20). The actin- high frequency of residual micrometastasis and relapse (7–10). binding proteins (ABP) vasodilator-stimulated phosphoprotein Overall, approximately 50% of surgically treated patients suffer (VASP), profilin 1, and cofilin 1 are key facilitators of actin dynamics (21–23). Under homeostatic conditions, VASP, profilin fi 1Center for Perinatal Research, The Research Institute at Nationwide 1, and co lin 1 are regulated through a feedback mechanism Children's Hospital, Columbus, Ohio. 2Department of Radiation Oncol- involving actin polymerization/stabilization or depolymeriza- ogy,The Ohio State University, Columbus, Ohio. 3Department of Pedi- tion/degradation. Profilin 1 recruits ATP-actin monomers to the atrics, The Ohio State University, Columbus, Ohio. proline-rich region (PPR) of VASP, a scaffolding ABP, and aids in Note: Supplementary data for this article are available at Molecular Cancer actin polymerization through the formation of long actin fila- Therapeutics Online (http://mct.aacrjournals.org/). ments. Alternatively, cofilin 1 binds to actin depolymerizing Corresponding Author: Mehboob Ali, Center for Perinatal Research, The factor (ADF) and disassembles actin filaments without capping Research Institute at Nationwide Children's Hospital, 700 Children's Drive, or by creating positive ends on the filament fragments. These RB-3, Columbus, OH 43205. Phone: 614-355-6748; Fax: 614-355-5896; E-mail: events involve an ATP-to-ADP exchange, which precipitates the [email protected] recycling of actin filaments to reassemble and polymerize. In doi: 10.1158/1535-7163.MCT-16-0092 response to changes in the cellular microenvironment, profilin Ó2016 American Association for Cancer Research. 1 converts the ADP-actin monomers to ATP-actin monomers to be 2220 Mol Cancer Ther; 15(9) September 2016 Downloaded from mct.aacrjournals.org on October 2, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 5, 2016; DOI: 10.1158/1535-7163.MCT-16-0092 ABPs Expression/Localization and DHA in Metastasis reused for actin polymerization. In this way, ABP-mediated actin therapeutic for inhibiting metastasis and prolonged cell viability dynamics regulate cellular homeostasis and maintain cytoskeletal through modulation of actin dynamics. structure (17, 21, 22, 24–31). During metastasis, actin cytoskeletal remodeling at the leading edges of cancer cells facilitate invasive organelle (lamelipodia, filopodia, and invadopodia) formation Materials and Methods and matrix degradation (15, 32–34). ABP expression and cellular localization in human lung biopsy The complexity of ABP regulation and the control of malignant samples (immunofluorescence staining) cell behaviors are demonstrated in Fig. 6. In cancer cells, especially Human lung cancer tissue slides were obtained from the Lung as they transform toward metastasis, dramatic changes occur Cancer Biospecimen Research Network (LCBRN), University disrupting internal signaling cascades, which in turn accelerate of Virginia (Charlottesville, VA). Normal (n ¼ 4) and malignant cellular machinery, including actin dynamics, to meet the (n ¼ 4) lung tissue slides were processed for immunofluores- demand for increased proliferation and migration. VASP can be cence labeling using standard protocols (45). Tissue sections phosphorylated at S157 via PKA (protein kinase A) or S239 via were stained with profilin 1, cofilin 1, VASP, and VASPpS239 PKG (protein kinase G). Under resting conditions, phosphoryla- (dilution, 1: 500) (Cell Signaling Technology, Inc.) and anti- tion of VASP at S157 promotes VASP activity while phosphory- human rabbit mAbs targeting VASPpS157 (dilution, 1: 500) lation at S239 facilitates homeostasis in the presence of a stimulus (Santa Cruz Biotechnology) followed by secondary antibodies due to changes in the cellular environment. Thus, actin polymer- Alexa 488–labeled IgG (1:1,000) and nuclei were stained with ization via VASPpS157 is prometastatic/antiapoptotic while DAPI (Invitrogen). Images (4 from each slide) were taken using VASPpS239 is antimetastatic/proapoptotic in cancer cells. A num- Carl Zeiss's Axio Scope A1 Polarized Light Fluorescent Micro- ber of ABPs, including profilin 1 and cofilin 1, are associated with scope (Carl Zeiss) with 400Â magnification and identical set- VASP and are likely involved in the metastatic process but their tings. Intensity of image color was quantified using NIH ImageJ interactions with each other and VASP are not fully understood. software using identical background settings. The results exp- The current investigation explores these associations and spec- ressed as intensity/cell. ulates that they constitute a "switch on or off" mechanism for actin dynamics and thus unregulated proliferation and migration. In Cell culture and treatment summary, we and others have shown VASPpS157 as procarcino- Invasive lung cancer cells (A549, ATCC CCL-185) were genic, promoting protrusion, remodeling, and cell survival (20, obtained from ATCC in fall of 2013. At the time of purchase, the 23, 35). In contrast, VASPpS239 has been shown to be anticarci- cells were cultured for two passages and frozen in liquid nitrogen nogenic, promoting F-actin depolymerization, cytoskeletal stabi- for future use. For the current experiments, a new vial was thawed lization, and apoptosis (23, 34). and the cells were authenticated at that time using the manufac- miRNAs are attractive molecular therapeutic targets against turer's recommendations, which included morphology, growth cancer growth and metastasis (36). miR-17-92, a cluster of six curve analyses, and mycoplasma detection. Cells used for the microRNAs encoded by a single transcript, is highly expressed in current studies were between passages 4–8 after purchase from the malignant tumors and may function as an oncogene by negatively vendor. Noninvasive lung epithelial cells (MLE12, ATCC CRL- regulating tumor suppressor genes and/or genes that control cell 2110) were obtained from ATCC in 2011. At the
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