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Identification of the Human PHLDA1/TDAG51 Gene: Down-Regulation in Metastatic Melanoma Contributes to Apoptosis Resistance and Growth Deregulation1

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Identification of the Human PHLDA1/TDAG51 Gene: Down-Regulation in Metastatic Melanoma Contributes to Apoptosis Resistance and Growth Deregulation1 [CANCER RESEARCH 62, 5920–5929, October 15, 2002] Identification of the Human PHLDA1/TDAG51 Gene: Down-Regulation in Metastatic Melanoma Contributes to Apoptosis Resistance and Growth Deregulation1 Ru¨diger Neef, Martina A. Kuske, Elma Pro¨ls, and Judith P. Johnson2 Institute for Immunology, Ludwig Maximilians University of Munich, Munich, Germany 80336 ABSTRACT are up-regulated or induced during melanoma development. Compar- ison of gene expression between human melanoma cell lines selected To identify molecules involved in the progression of human melanoma for high and low metastatic behavior in immune-deficient mice has to metastatic disease, autologous primary and metastatic melanoma cells were compared by differential mRNA display. One cDNA, expressed in also led to the identification of molecules up-regulated in metastatic primary but not in autologous metastatic cells in three different patients, cells in vivo, for example the cell adhesion molecule ALCAM (11), was cloned and characterized, and shown to be the human homologue of melanoma inhibitory activity (12), and the GTPase RhoC (13). The the inducible, immediate early TDAG51/PHLDA1 (pleckstrin-homology- comparison of gene expression between syngeneic benign and malig- like domain family A, member1) gene. Monoclonal antibodies produced nant murine melanocytic cells has led to the identification of genes against the PHLDA1 protein revealed homogeneous strong expression by such as annexin-VI that are also differentially expressed in human benign melanocytic nevi, and progressively reduced expression in primary melanocytic lesions in vivo (14). In the study reported here, gene and metastatic melanomas in vivo. Analysis of stable cDNA transfectants in two different cell lines revealed that constitutive PHLDA1 expression is expression in cells derived from primary and metastatic lesions of the associated with reduced cell growth, cloning efficiency, and colony for- same patient has been compared using mRNA differential display mation but not with alterations in cell cycle parameters. However, (15). This approach has led to the identification of the human homo- PHLDA1 expression was associated with increased basal apoptosis as logue of the TDAG51/PHLDA13 gene (16). The expression of this assessed by live cell annexin V binding, terminal deoxynucleotidyltrans- gene was down-regulated in metastatic as compared with primary ferase-dependent nucleotide incorporation, and with increased cleavage of melanoma cells in three different patients. PHLDA1/TDAG51, iden- poly(ADP-ribose) polymerase and caspase-9. Constitutive PHLDA1 ex- pression greatly enhances the sensitivity of human melanoma cells to the tified previously in murine T lymphocytes where it is required for chemotherapeutic agents doxorubicin and camptothecin. These results activation induced cell death (17), is here shown to be expressed suggest that PHLDA1 is constitutively expressed by melanocytic nevi in human benign melanocytic nevi and to be progressively down- where it may contribute to their benign phenotype. The progressive loss of regulated in primary and metastatic melanomas. Analysis of cDNA PHLDA1 expression in melanomas may play a role in deregulated cell transfectants indicates that constitutive PHLDA1 expression in mela- growth and apoptosis resistance in these tumors. nocytic cells is associated with increased apoptosis sensitivity and with reduced growth. These results suggest that changes in the ex- INTRODUCTION pression of PHLDA1 in melanocytic cells may contribute to the progression of malignant melanomas. The progression of human tumors to systemic, metastatic disease is responsible for the majority of cancer-associated morbidity and mor- tality. The identification of molecules contributing to this process can MATERIALS AND METHODS lead to an understanding of critical pathways involved as well as to potential targets for therapeutic intervention (1). Malignant melanoma Cell Lines and Tissues is a rapidly metastasizing, therapy-resistant tumor, which is increasing Cell lines were obtained from the ATCC (Manassas, VA), established in our in incidence (2, 3). Because of their pigmented nature and epidermal laboratory or obtained through exchange. The autologous cell lines GT-BS and location, a variety of benign and malignant melanocytic lesions have GU-BSA were established from a primary nodular melanoma and a lymph been identified and ordered into a scheme of distinct stages, which is node metastasis, respectively (18), and were kindly provided by Monika proposed to reflect the development and progression of malignant Vetterlein, Institute for Tumor Biology and Cancer Research, University of melanoma (4, 5). Despite extensive histopathological and clinical Vienna, Vienna, Austria. WM-115 and WM-266–4 were obtained from analyses, the changes in gene expression and subsequent functional ATCC, and IgR37 and IgR39 from Stefan Carrell (deceased); Swiss Institute consequences that characterize these stages are only beginning to be for Experimental Cancer Research, ISREC, Epalinges, Switzerland. All of the defined. Different approaches have been used to identify changes in cells were maintained in RPMI 1640 with 5–10% FCS, 1 mM sodium pyruvate, gene expression during melanoma development. Comparison of mela- and antibiotics. Cells were stimulated with 10 ng/ml PMA (Sigma Chemical nocytic protein expression in different stages has led to the identifi- Co.) for 24 h, or exposed to 2 ␮g/ml camptothecin (Sigma) or 1 ␮g/ml cation of several molecules, which appear to play a role in the doxorubicin (Sigma) for the indicated times. progression of this tumor in in vivo models. These include ␤3 integrin Tissue specimens and histological diagnoses were obtained from the Der- (6, 7) and the cell adhesion molecule MCAM/MUC18 (8–10), which matology Departments of the University of Hamburg (Hamburg, Germany), the University of Munich, and the Technical University of Munich (Munich, Germany). Tissue specimens were frozen in liquid nitrogen shortly after Received 1/30/02; accepted 8/15/02. Ϫ The costs of publication of this article were defrayed in part by the payment of page removal and stored at 80°C. charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by grants from the Deutsche Krebshilfe, Mildred Scheel Stiftung, W137/ 3 The abbreviations used are: PHLDA1, pleckstrin-homology-like domain family A, 94/Jo1. This work was presented in part at the 92nd annual meeting of the AACR (2001) member 1; ATCC, American Type Culture Collection; PMA, phorbol 12-myristate and at the 32nd Annual Meeting of the German Society of Immunology (2001). 13-acetate; RT-PCR, reverse transcription-PCR; GST, glutathione S-transferase; TUNEL, 2 To whom requests for reprints should be addressed, at Institute for Immunology, terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling; MTT, 3-(4,5- Goethestrasse 31, 80336 Munich, Germany. Phone: 49-89-5996-660; Fax: 49-89-5160- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; neo, neomycin-resistant; PARP, 2236; E-mail: [email protected]. poly(ADP-ribose) polymerase; FACS, fluorescence-activated cell sorter. 5920 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2002 American Association for Cancer Research. FUNCTION OF PHLDA1/TDAG51 IN HUMAN MELANOMA Differential Display and Isolation of Full-Length P7 cDNA Signaling), and peroxidase-coupled second antibodies (Dako), and bound enzyme activity detected with a chemiluminescence substrate (ECL; Amer- Total RNA was extracted from GT-BS and GU-BSA cells using RNAzol sham Bioscience). Goat antiserum against human TDAG51/PHLDA1 was (Wacker Chemie, Munich, Germany). Using the RNAmap kit (GenHunter, obtained from Santa Cruz Laboratories (L-19; Santa Cruz, CA), and mono- ␮ Nashville, TN), 0.2 g of total RNA was reverse transcribed with the oligode- clonal antibody RN-6E2 (IgG2a) directed against the human PHLDA1 mole- oxythymidylic acid primers T12MA, T12MC, or T12MG and subsequently cule was produced in our laboratory. To control for loading and transfer the amplified by PCR combining each of the three different T MM primers with 12 filters were stripped [0.1 M glycine (pH 2.9), 2 ϫ 20 min] and reprobed with Ј Ј Ј the five arbitrary primers AP-1 (5 -AGCCAGCGAA-3 ), AP-2 (5 -GAC- antiactin antibody (A5441, IgG1; Sigma). CGCTTGT-3Ј), AP-3 (5Ј-AGGTGACCGT-3Ј), AP-4 (5Ј-GGTACTCCAC- 3Ј), and AP-5 (5Ј-GTTGCGATCC-3Ј). Three independent reverse transcrip- Apoptosis Assays, Cell Cycle Analysis tion and PCR reactions were performed and the [33P]ATP-labeled amplification products separated on a 6% denaturing polyacrylamide gel. Apoptosis was assessed by annexin V binding in the presence of propidium Differentially amplified PCR products were cut out from the dried gel, ream- iodide to distinguish living and dead cells, and by TdT-dependent dUTP plified, and cloned into the pCRII vector (Invitrogen, Groningen, Netherlands). incorporation (TUNEL). Assessment of apoptosis was performed on cells that The 350-bp P7 differential display fragment was used to screen a melanoma were ϳ70% confluent. Binding of FITC-annexin V was performed according ␭ (Mel JuSo) cDNA library in ZAP (Ref. 8; Stratagene, La Jolla, CA), and two to the manufacturer’s instructions (Apoptosis Detection kit; BD PharMingen, overlapping clones of 3.0 and 2.7 kb were isolated. Neither clone contained an San Diego, CA). TUNEL assays were performed using
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