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Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis

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Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis Published OnlineFirst October 10, 2011; DOI: 10.1158/0008-5472.CAN-11-2015 Cancer Therapeutics, Targets, and Chemical Biology Research Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis Junghee Lim1,3, Giyong Jang1, Seeun Kang1, Guewha Lee1, Do Thi Thuy Nga2, Do Thi Lan Phuong2, Hyuncheol Kim3, Wael El-Rifai4, H. Earl Ruley5, and Daewoong Jo1,2,4 Abstract Occult metastases are a major cause of cancer mortality, even among patients undergoing curative resection. Therefore, practical strategies to target the growth and persistence of already established metastases would provide an important advance in cancer treatment. Here, we assessed the potential of protein therapy using a cell permeable NM23-H1 metastasis suppressor protein. Hydrophobic transduction domains developed from a screen of 1,500 signaling peptide sequences enhanced the uptake of the NM23 protein by cultured cells and systemic delivery to animal tissues. The cell-permeable (CP)-NM23 inhibited metastasis-associated phenotypes in tumor cell lines, blocked the establishment of lung metastases, and cleared already established pulmonary metastases, significantly prolonging the survival of tumor-bearing animals. Therefore, these results establish the potential use of cell-permeable metastasis suppressors as adjuvant therapy against disseminated cancers. Cancer Res; 71(23); 7216–25. Ó2011 AACR. Introduction primary tumors (3). NME1, the first reported metastasis suppressor gene, was initially characterized as nucleoside Metastasis is an acquired and separately evolving pheno- diphosphate kinase (NDK), an enzyme required to maintain type that enables cancer cells to disseminate and grow at cellular pools of nucleoside triphosphates. Interest in NDK locations distant from the primary tumor site. For many as a metastasis suppressor (alternatively named NM23-H1 or tumors, the molecular changes responsible for initiating NM23) was prompted by studies describing inverse correla- metastatic spread have already occurred by the time of tions between NM23 expression and metastatic potential, initial diagnosis, and are ultimately responsible for most first in melanoma cells (4) and later in other types of tumors cancer deaths (1, 2). Effective strategies to target dissemi- (5). Subsequent gene transfer experiments documented the nated tumors are therefore expected to have tremendous ability of NM23 to suppress metastasis-associated pheno- therapeutic benefit. types both in cultured cells and in animal metastasis models In principle, antimetastasis therapies could either block (6–10). The precise mechanism by which NM23 influences activities required for the growth or survival of disseminated metastasis is not understood, in part, because the protein cancer cells or restore the expression and/or activity of possesses multiple enzymatic activities that directly or proteins that function to suppress metastasis. The latter indirectly suppress mitogen-activated protein kinase includes more than 20 metastasis suppressors—proteins (MAPK) signaling (11, 12); regulate small G-protein func- that selectively inhibit the seeding, growth, or persistence tions important in cell motility, cytoskeletal reorganization, of metastatic foci while having only limited effects on and cell adhesion (13–15); and influence genome mainte- nance (16, 17). Nevertheless, clinical trials based on hor- monal activation of endogenous NM23 expression are cur- fi 1 Authors' Af liations: ProCell R&D Institute, ProCell Therapeutics, Inc., rently in progress (4). Seoul; 2Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju; and 3Interdisciplinary Program of Integrated In the present study, we describe an antimetastasis therapy Biotechnology, Sogang University, Seoul, Korea; and Departments of based on the systemic delivery of a cell penetrating NM23-H1 4Surgery and Cancer Biology and 5Microbiology and Immunology, Van- derbilt University School of Medicine, Nashville, Tennessee protein. For this experiment, we developed novel macromol- ecule transduction domains (MTD) modeled after hydropho- Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). bic signal peptides previously shown to promote protein uptake by cultured cells and animal tissues (18). The MTD- Corresponding Author: Daewoong Jo, Department of Surgery, Vanderbilt University School of Medicine 1255 MRB IV, 2215B Garland Avenue, NM23 inhibited metastasis-associated phenotypes in tumor Nashville, TN 37232. Phone: 615-322-8207; Fax: 615-322-7852; E-mail: cell lines and not only suppressed the establishment of lung [email protected] metastases but also cleared previously established metastases, doi: 10.1158/0008-5472.CAN-11-2015 significantly prolonging the survival of animals harboring Ó2011 American Association for Cancer Research. disseminated tumor cells. 7216 Cancer Res; 71(23) December 1, 2011 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst October 10, 2011; DOI: 10.1158/0008-5472.CAN-11-2015 Cell-Permeable Tumor Metastasis Suppressor NM23 A Treatment (10 µmol/L) MDA-MB-435 Proteins - HN HM76N HNM76 HM77N HNM77 p-MEK ratio 1.0 0.7 0.9 0.6 0.6 0.4 Figure 1. Inhibition of MAPK p-ERK signaling and EDG2 expression by CP-NM23. MDA-MB-435 (A), MDA- ratio 1.0 1.3 1.0 0.3 0.2 0.4 MB-231 (B), and A549 cells (C) were β-Actin treated for 1 hour with 10 mmol/L of the indicated recombinant NM23 proteins. Cell lysates, prepared B C immediately (p-MEK and p-ERK) or after 8 hours (EDG2) were Treatment Treatment MDA-MB-231 A549 immunoblotted with antibodies (10 µmol/L) (10 µmol/L) against the indicated proteins. ERK, HN HM N HNM Proteins - HN HM77N HNM77 Proteins - 77 77 extracellular signal-regulated kinase; MEK, MAP/ERK kinase. p-MEK p-MEK ratio 1.0 1.0 < < ratio 1.0 2.3 < <a p-ERK p-ERK ratio 1.0 1.1 < < ratio 1.0 2.2 < < EDG2 EDG2 ratio 1.0 1.0 < < ratio 1.0 2.9 < < β-Actin β-Actin Materials and Methods Analysis of protein uptake in cultured cells Recombinant proteins were conjugated to 5/6-fluorescein Preparation of recombinant MTD-fused proteins isothiocynate (FITC), according to the manufacturer's instruc- MTD-76 and MTD-77 were identified from a screen of 1,500 tions (Pierce Chemical). RAW 264.7 cells were treated with 10 signaling peptides for sequences with protein transduction mmol/L FITC-labeled proteins for 1 hour at 37C, washed 3 activity. Sequences spanning amino acids 8 to 30 of NP631283 times with cold PBS, treated with proteinase K (10 mg/mL) for (FLIAGVIVALLAVFTVVRAVRIV) and 1 to 23 of NP003231 20 minutes at 37C to remove cell-surface bound proteins, and (MWPLWLCWALWVLPLAGPGAALT) were subsequently subjected to FACS analysis (FACSCalibur; Becton Dickinson). modified (D. Jo et al.; manuscript in preparation), generating Each experiment was conducted at least 3 times. ALVLPLAP and AVALLILAV, respectively. Coding sequences Experiments to visualize protein uptake were conducted in for NM23 and enhanced GFP (EGFP) fusion proteins were much the same manner except that NIH3T3 cells were exposed þ cloned into pET-28a (Novagen) from PCR-amplified DNA to 10 mmol/L FITC-proteins for 30 minutes and then nuclei segments (Supplementary Table S1). The recombinant pro- or plasma membranes were counter stained with 1 mg/mL teins were purified from Escherichia coli BL21-CodonPlus propidium iodide (Sigma-Aldrich) or 5 mg/mL FM4-64 (DE3) cells grown at an A600 of 0.6 and induced for 2 hours (Molecular Probes), respectively. The cells were washed 3 times with 0.7 mmol/L Isopropyl b-D-1-thiogalactopyranoside with cold PBS and examined by confocal laser scanning (IPTG). Denatured Â6 histidine-tagged recombinant proteins microscopy. þ were purified by Ni2 affinity chromatography as directed by the supplier (Qiagen). After purification, they were Systemic delivery of MTD fusion proteins dialyzed against a refolding buffer (0.55 mol/L guanidine HCl, Six-week-old Balb/c female mice were injected intraperito- 0.44 mol/L L-arginine, 50 mmol/L Tris-HCl, 150 mmol/L NaCl, 1 neally (300 mg/head) with FITC only, FITC-conjugated EGFP, mmol/L EDTA, 100 mmol/L NDSB, 2 mmol/L reduced gluta- or NM23 recombinant proteins. After 2 hours, the liver, kidney, thione, and 0.2 mmol/L oxidized glutathione) and then spleen, lung, heart, and brain were isolated, infused with O.C.T. against a physiologic buffer such as RPMI-1640 medium. compound (Sakura), and frozen on dry ice. Cryosections H, N, and M stand for the His tag, NM23, and MTD, respectively. (20-mm thickness) were analyzed by fluorescence microscopy. Histidine-tagged recombinant NM23 proteins were HN (His- Alternatively, the uptake of FITC-NM23 proteins was assessed NM23), HM76N (His-MTD76-NM23), HNM76 (His-MTD76- after 1 and 2 hours by fluorescence-activated cell sorting NM23), HM77N (His-MTD77-NM23), and HNM77 (His-NM23- (FACS) analysis of unfixed blood leukocytes/lymphocytes or MTD77). total splenocytes. www.aacrjournals.org Cancer Res; 71(23) December 1, 2011 7217 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst October 10, 2011; DOI: 10.1158/0008-5472.CAN-11-2015 Lim et al. A Cells only HN Cells only HN HM N HNM HM N HNM 76 76 77 77 HM76N HNM76 HM77N HNM77 Figure 2. CP-NM23 suppresses cell invasion and migration. A, Matrigel 600 MDA-MB-435 600 MDA-MB-231 invasion assay. Tumor cells were treated for 1 hour with the indicated 500 500 proteins (10 mmol/L); after 24 hours, 400 400 cells penetrating and migrating to ** the basal side of Matrigel-coated 300 300 membranes were visualized (top) * * and counted (bottom). The data are 200 200 presented as means Æ SD (n ¼ 3), Invaded cell number * Invaded cell number à P < Ãà P < * * , 0.01; , 0.05, as 100 100 determined by the Student unpaired t test. B, wound-healing 0 0 ly N 6 N 7 assay. Cell monolayers, treated n 7 77 6N 7 H M H 7 NM M NM B HM76N H HM77N HN H HNM76 HM77N H with NM23 proteins as in (A), were Cells o Cells only scraped to create a "wound" devoid MDA-MB-435 MDA-MB-231 of cells (dashed lines) and 0 h 24 h 0 h 24 h photographed after 24 hours.
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