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Inhibits Growth and Migration of Human Melanoma Cells and Elicits PTEN Elevation and Inactivation of PI3K/AKT Signaling

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Inhibits Growth and Migration of Human Melanoma Cells and Elicits PTEN Elevation and Inactivation of PI3K/AKT Signaling University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Faculty Publications and Other Works -- UT University of Tennessee Graduate School of Graduate School of Medicine Medicine 5-7-2013 Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling James S. Foster University of Tennessee - Knoxville Lindsay M. Fish University of Tennessee - Knoxville Jonathan E. Phipps University of Tennessee - Knoxville Charles T. Bruker James M. Lewis University of Tennessee - Knoxville See next page for additional authors Follow this and additional works at: https://trace.tennessee.edu/utgradmedpubs Part of the Microbiology Commons, and the Oncology Commons Recommended Citation BMC Cancer 2013, 13:227 doi:10.1186/1471-2407-13-227 This Article is brought to you for free and open access by the University of Tennessee Graduate School of Medicine at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Faculty Publications and Other Works -- UT Graduate School of Medicine by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Authors James S. Foster, Lindsay M. Fish, Jonathan E. Phipps, Charles T. Bruker, James M. Lewis, John L. Bell, Alan Solomon, and Daniel P. Kestler This article is available at TRACE: Tennessee Research and Creative Exchange: https://trace.tennessee.edu/ utgradmedpubs/2 Foster et al. BMC Cancer 2013, 13:227 http://www.biomedcentral.com/1471-2407/13/227 RESEARCH ARTICLE Open Access Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling James S Foster1,3†, Lindsay M Fish2,3†, Jonathan E Phipps1,3, Charles T Bruker4, James M Lewis2,3, John L Bell2,3, Alan Solomon1,3 and Daniel P Kestler1,3* Abstract Background: The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity. Herein we have extended these studies to the effects of ODAM on cultured melanoma cell lines. Methods: The A375 and C8161 melanoma cell lines were stably transfected with ODAM and assayed for properties associated with tumorigenicity including cell growth, motility, and extracellular matrix adhesion. In addition, ODAM–transfected cells were assayed for signal transduction via AKT which promotes cell proliferation and survival in many neoplasms. Results: ODAM expression in A375 and C8161 cells strongly inhibited cell growth and motility in vitro, increased cell adhesion to extracellular matrix, and yielded significant cytoskeletal/morphologic rearrangement. Furthermore, AKT activity was downregulated by ODAM expression while an increase was noted in expression of the PTEN (phosphatase and tensin homolog on chromosome 10) tumor suppressor gene, an antagonist of AKT activation. Increased PTEN in ODAM-expressing cells was associated with increases in PTEN mRNA levels and de novo protein synthesis. Silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing melanoma cells. Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN-deficient BT-549 breast cancer cells. Conclusions: The apparent anti-neoplastic effects of ODAM in cultured melanoma and breast cancer cells are associated with increased PTEN expression, and suppression of AKT activity. This association should serve to clarify the clinical import of ODAM expression and any role it may serve as an indicator of tumor behavior. * Correspondence: [email protected] †Equal contributors 1Department of Medicine, Human Immunology and Cancer Program, University of Tennessee Health Sciences Center-Knoxville, 1924 Alcoa Highway, Knoxville, TN 37920, USA 3Graduate School of Medicine, University of Tennessee Health Sciences Center-Knoxville, 1924 Alcoa Highway, Knoxville, TN 37920, USA Full list of author information is available at the end of the article © 2013 Foster et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Foster et al. BMC Cancer 2013, 13:227 Page 2 of 11 http://www.biomedcentral.com/1471-2407/13/227 Background a construct encoding ODAM and evaluated in vitro for Melanoma is the most lethal form of skin cancer and properties associated with tumorigenesis. Similar to our the incidence is increasing in the United States and earlier studies with breast cancer cells, the results indi- worldwide [1]. Mortality from melanoma occurs as a cate that ODAM expression inhibits cell growth and mi- result of local tumor proliferation and invasion of sur- gration in melanoma cells. We further demonstrate that rounding tissues leading to metastatic spread of the this inhibition is associated with increased expression of disease. Clinically, metastases are often predicted by pri- the PTEN (phosphatase and tensin homolog on chromo- mary tumor factors that reflect biologic behavior such as some 10) tumor suppressor and suppression of signaling Breslow thickness, mitotic rate, and ulceration. Sentinel via AKT, in both of the melanoma cell lines as well as in lymph node (SLN) status remains the single most im- MDA-MB-231 breast cancer cells. portant predictor of survival [2]. Recently, multiple po- tential biomarkers for melanoma have been identified; Methods however, their clinical significance remains largely to be Cells and tissue culture determined [3-5]. On a molecular and genetic level, a The human melanoma cell line C8161 [20] was kindly number of factors influencing primary melanoma growth provided by Professor Mary JC Hendrix. The A375 mel- and metastasis have been identified, including signaling anoma cell line and BT-549 breast cancer line were via the phosphoinositide 3-kinase (PI3K)/AKT/mamma- obtained from the American Type Culture Collection lian target of rapamycin (mTOR), and Wnt/β-catenin (Rockville, MD). Control and ODAM-expressing MDA- pathways, as well as BRAF mutations which activate sig- MB-231 cells were described in detail previously [18]. naling through the Ras/Raf/MAP-ERK kinase (MEK)/ All cell cultures were maintained in DMEM/F12 medium mitogen-activated protein kinase (/MAPK) pathway [6-9]. (Lonza, Walkersville, MD) containing 5% fetal bovine The Odontogenic Ameloblast-Associated Protein (ODAM) serum (FBS, Thermo-Fisher-Hyclone, Logan, UT), and was first identified less than a decade ago as the protein penicillin/streptomycin (Thermo-Fisher, Pittsburg, PA) in constituent of calcifying epithelial odontogenic/Pindborg a humidified incubator at 37°C under 5% CO2. These tumors (CEOT) and subsequent studies revealed that it is studies did not involve human or animal subjects but all highly expressed in mature ameloblasts and present in the studies were carried out under the oversight of our Insti- rodent enamel organ and junctional epithelium [10-13]. It tutional Review Board (approval numbers 2683 and 2803), has also been found to be present in additional normal hu- Biosafety Commitee (approval numbers 251-11 and 334- man tissues including the skin, gastrointestinal tract, tra- 11), and Animal Care and Use Commitee (approval num- chea, bronchus, and glandular breast epithelium. Further ber 2092-0412). analysis showed that ODAM is also expressed in epithelial malignancies including those of the, colon, breast, lung, Transfection of tumor cell lines with rODAM stomach, and in melanoma [14-16]. In breast cancer pa- The C8161, A375, and BT-549 cell lines were transfected tient biopsies a correlation was observed between ODAM with either a human ODAM-pcDNA5T/O construct [18] expression/localization and disease staging/clinical out- or, the empty vector control using Lipofectamine LTX come, indicating that ODAM may serve as a novel prog- reagent (Invitrogen, Carlsbad, CA) according to the man- nostic biomarker in this type of cancer [17]. When stably ufacturer’s protocol. Selection of stable ODAM-producing transfected with recombinant ODAM the MDA-MB-231 clones was performed in medium supplemented with breast cancer cell line showed marked inhibition of neo- 400 μg/mL hygromycin (Thermo-Fisher-Hyclone) in plastic and metastatic properties in vivo and in vitro [18]. 100-mm culture dishes and visible colonies transferred This suggests that ODAM has a potentially significant role into 24-well plates. Culture media collected 7–10 days in regulating tumorigenesis and metastasis in breast cancer later were tested for ODAM production by capture with possible clinical implications. More recently, a retro- ELISA [18]. ODAM-positive clones were designated as spective study of melanoma patient samples have demon- C8161-ODAM, A375-ODAM, BT-549-ODAM, and along strated a significant correlation of ODAM expression/ with respective controls were expanded and maintained in nuclear localization and sentinel lymph node metastases medium with hygromycin. indicative of poorer prognosis [19]. The apparent association of
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