Uteroglobin (UG) Suppresses Extracellular Matrix Invasion by Normal and Cancer Cells That Express the High Affinity UG-binding Proteins

Abstract

Uteroglobin (UG) is a steroid-inducible, multifunctional, secreted protein with antiinflammatory and antichemotactic properties. Recently, we have reported a high affinity UG-binding protein (putative receptor), on several cell types, with an apparent molecular mass of 190 kDa (Kundu, G. C., Mantile, G., Miele, L., Cordella-Miele, E., and Mukherjee, A. B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2915–2919). Since UG is a homodimer in which the 70 amino acid subunits are connected by two disulfide bonds, we sought to determine whether UG monomers also interact with the 190-kDa UG-binding protein and if so, whether it has the same biological activity as the dimer. Surprisingly, we discovered that in addition to the 190-kDa species, another protein, with an apparent molecular mass of 49 kDa, binds reduced UG with high affinity and specificity. Both 49- and 190-kDa proteins are readily detectable on nontransformed NIH 3T3 and some murine cancer cells (e.g. mastocytoma, sarcoma, and lymphoma), while lacking on others (e.g. fibrosarcoma). Most interestingly, pretreatment of the cells, which express the binding proteins, with reduced UG dramatically suppresses extracellular matrix (ECM) invasion, when such treatment had no effect on fibrosarcoma cells that lack the UG-binding proteins. Tissue-specific expression studies confirmed that while both 190- and 49-kDa UG-binding proteins are present in bovine heart, spleen, and the liver, only the 190-kDa protein is detectable in the trachea and in the lung. Neither the 190-kDa nor the 49-kDa protein was detectable in the aorta. Purification of these binding proteins from bovine spleen by UG-affinity chromatography and analysis by SDS-polyacrylamide gel electrophoresis followed by silver staining identified two protein bands with apparent molecular masses of 40 and 180 kDa, respectively. Treatment of the NIH 3T3 cells with specific cytokines (i.e. interleukin-6) and other agonists (i.e.lipopolysaccharide) caused a substantially increased level of125I-UG binding but the same cells, when treated with platelet-derived growth factor, tumor necrosis factor-α, interferon-γ, and phorbol 12-myristate 13-acetate, did not alter the UG binding. Taken together, these findings raise the possibility that UG, through its binding proteins, plays critical roles in the regulation of cellular motility and ECM invasion. Uteroglobin (UG) is a steroid-inducible, multifunctional, secreted protein with antiinflammatory and antichemotactic properties. Recently, we have reported a high affinity UG-binding protein (putative receptor), on several cell types, with an apparent molecular mass of 190 kDa (Kundu, G. C., Mantile, G., Miele, L., Cordella-Miele, E., and Mukherjee, A. B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2915–2919). Since UG is a homodimer in which the 70 amino acid subunits are connected by two disulfide bonds, we sought to determine whether UG monomers also interact with the 190-kDa UG-binding protein and if so, whether it has the same biological activity as the dimer. Surprisingly, we discovered that in addition to the 190-kDa species, another protein, with an apparent molecular mass of 49 kDa, binds reduced UG with high affinity and specificity. Both 49- and 190-kDa proteins are readily detectable on nontransformed NIH 3T3 and some murine cancer cells (e.g. mastocytoma, sarcoma, and lymphoma), while lacking on others (e.g. fibrosarcoma). Most interestingly, pretreatment of the cells, which express the binding proteins, with reduced UG dramatically suppresses extracellular matrix (ECM) invasion, when such treatment had no effect on fibrosarcoma cells that lack the UG-binding proteins. Tissue-specific expression studies confirmed that while both 190- and 49-kDa UG-binding proteins are present in bovine heart, spleen, and the liver, only the 190-kDa protein is detectable in the trachea and in the lung. Neither the 190-kDa nor the 49-kDa protein was detectable in the aorta. Purification of these binding proteins from bovine spleen by UG-affinity chromatography and analysis by SDS-polyacrylamide gel electrophoresis followed by silver staining identified two protein bands with apparent molecular masses of 40 and 180 kDa, respectively. Treatment of the NIH 3T3 cells with specific cytokines (i.e. interleukin-6) and other agonists (i.e.lipopolysaccharide) caused a substantially increased level of125I-UG binding but the same cells, when treated with platelet-derived growth factor, tumor necrosis factor-α, interferon-γ, and phorbol 12-myristate 13-acetate, did not alter the UG binding. Taken together, these findings raise the possibility that UG, through its binding proteins, plays critical roles in the regulation of cellular motility and ECM invasion. Some of the most important biological processes, such as inflammation, wound healing, embryo implantation, and cancer cell metastasis, involve cellular migration and invasion of the extracellular matrix (ECM). 1The abbreviations used are: ECMextracellular matrixUGuteroglobinhUGhuman UGDSSdisuccinimidyl suberateIFN-γinterferon-γLPSlipopolysaccharidePAGEpolyacrylamide gel electrophoresisHBSSHanks' balanced salt solutionPBSphosphate-buffered salineFnfibronectin.However, the mechanisms that regulate these processes are not clearly understood. Recent studies have focused on understanding the receptor-mediated pathways that play critical roles in regulating cellular motility and invasion of the ECM. extracellular matrix uteroglobin human UG disuccinimidyl suberate interferon-γ lipopolysaccharide polyacrylamide gel electrophoresis Hanks' balanced salt solution phosphate-buffered saline fibronectin. More than three decades ago, a steroid-inducible secreted protein in the uterus of pregnant rabbits was discovered and was named blastokinin by Krishnan and Daniel (1Krishnan R.S. Daniel Jr., J.C. Science. 1967; 158: 490-492Crossref PubMed Scopus (233) Google Scholar) and uteroglobin (UG) by Beier (2Beier H.M. Biochim. Biophys. Acta. 1968; 160: 289-291Crossref PubMed Scopus (242) Google Scholar). Several years later it was recognized that this protein, detectable in nearly all vertebrates, inhibits phospholipase A2 (EC 3.1.1.4) activity (3Levin S.W. Butler J.D. Schumacher U.K. Wightman P.D. Mukherjee A.B. Life Sci. 1986; 38: 1813-1819Crossref PubMed Scopus (180) Google Scholar, 4Miele L. Cordella-Miele E. Facchiano A. Mukherjee A.B. Nature. 1988; 335: 726-730Crossref PubMed Scopus (205) Google Scholar, 5Facchiano A. Cordella-Miele E. Miele L. Mukherjee A.B. Life Sci. 1991; 48: 453-464Crossref PubMed Scopus (42) Google Scholar, 6Cabre F. Moreno J.J. Carabaza A. Ortega E. Mauleon D. 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It is now that the of UG, from all are to the and has the to interact with other (e.g. binding Mol. Cell. Endocrinol. 1989; PubMed Scopus Google Scholar) have reported an of UG from the of the uterus the of the rabbit the possibility that a UG-binding protein present on the have reported that UG binds to a protein with a molecular mass of 190 kDa, on several cell types, including the with high affinity and G. Miele L. Cordella-Miele E. Mukherjee A.B. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). we that human UG and affinity with disuccinimidyl suberate we identified a UG-binding protein with a molecular mass of 49 kDa, in addition to the reported 190 kDa of the binding proteins from bovine spleen by UG affinity chromatography and analysis by and silver staining identified two proteins with apparent molecular masses of 40 and 180 kDa, both of these proteins are also readily detectable in the heart, and the but only the 190-kDa protein is detectable in the trachea and the while in the are treatment of the NIH 3T3 cells with specific cytokines and other agents (e.g. the of UG-binding protein bands while treatment of the same cells with platelet-derived growth factor, tumor necrosis factor-α, and phorbol 12-myristate to and both and reduced UG dramatically the invasion of ECM by NIH murine mastocytoma, sarcoma, and but not of fibrosarcoma while mastocytoma, sarcoma, and cells to express the UG-binding proteins, in fibrosarcoma Taken together, these raise the possibility that plays critical roles in regulating cellular of both and some cancer cells, in its high affinity binding proteins. was expressed in E. and to to the of G. Miele L. Cordella-Miele E. Singh G. Katyal S.L. Mukherjee A.B. J. Biol. Chem. 1993; 268: PubMed Google Scholar). was from invasion from cells mastocytoma, sarcoma, and in with and 10 in a of and as G. Miele L. Cordella-Miele E. Mukherjee A.B. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, A. S. G. S. A. Res. Google Scholar). cells mastocytoma, sarcoma, and with and and cells in of the invasion was with which was used as a was with with cells in the of the invasion in the presence of reduced and in a cells that the and to the of the with of the was with to and was with the cells an and by a M. UG was and was in of 10 and was by chromatography specific activity of was cells mastocytoma, sarcoma, and in with and with of in of Hanks' balanced salt solution bovine in the presence of reduced UG was reduced in presence of 10 was by of and the cells three with and in followed by addition of an of was by with a of specific binding was by the binding from the binding. binding by the cells mastocytoma, sarcoma, and in with and with reduced in of bovine in the presence of reduced UG with the cells with in of was by and cells by and in of solution and by in and on SDS-polyacrylamide gel with in a gel and from bovine heart, spleen, liver, and the aorta. of proteins from different tissues with reduced in bovine in the presence of reduced UG binding as with and the NIH 3T3 cells treated with different cytokines and other treated cells with reduced in and as bovine spleen tissue was in 10 was 10 was with 10 and by was by and to UG affinity UG affinity was to the of the UG protein was from the 10 and and with the UG-binding proteins was by binding and affinity of the was by followed by silver staining have that human UG in its binds to a protein on human cells with a molecular mass of 190 kDa with high affinity and G. Miele L. Cordella-Miele E. Mukherjee A.B. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). Since UG is a homodimer in which the 70 amino acid subunits are by two disulfide bonds, we sought to determine whether both reduced and UG with the same 190-kDa UG-binding we both the and reduced human UG on nontransformed NIH 3T3 and cancer sarcoma, and cell analysis of binding of the presence of a of specific binding with of NIH 3T3 cells have also binding on mastocytoma, sarcoma, and cells, and the but was no such binding when fibrosarcoma cells used not also the with of mastocytoma, sarcoma, and cells, not of the UG binding on these cells, we affinity studies with in the presence of a 49-kDa protein in addition to the identified 190-kDa G. Miele L. Cordella-Miele E. Mukherjee A.B. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). Both 49- and 190-kDa protein bands when human UG was to the to binding and affinity in the of no protein bands in the was we only a 190-kDa protein NIH 3T3 G. Miele L. Cordella-Miele E. Mukherjee A.B. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar), mastocytoma, sarcoma, and cells not Neither the 49-kDa nor the 190-kDa bands when fibrosarcoma cells with reduced not an to the UG-binding proteins, we used bovine tissues and affinity to determine if such tissues express these proteins. the cell we both the 49- and 190-kDa protein bands in bovine heart, spleen, and the liver, while in the trachea and in the only the 190-kDa protein was Neither the 190-kDa nor the 49-kDa was detectable in bovine to these proteins, we chromatography a human UG affinity bovine spleen and the proteins from the by the of the the proteins by followed by silver two proteins, with an apparent molecular mass of 40 and 180 kDa, clearly and affinity that both binding proteins interact not It is not this whether the two protein bands that reduced UG are subunits of the UG protein, if the molecular kDa) is a in which the UG-binding presence of both 190- and 49-kDa bands in the heart, spleen, and the and the of the 49-kDa in the trachea and the that the 49-kDa is a than a of the 190-kDa it was a the of and we have the 49-kDa in the trachea and as cDNA and which of the two is addition to the two protein bands we also a with an apparent molecular mass of this did not not that this an a of the 49- 190-kDa proteins that not the UG binding. Taken together, these that UG binds to several cell with high affinity and and this binding is by one protein with two subunits and 190 kDa) are two binding UG-binding UG-binding proteins UG affinity proteins by and and the protein bands by silver that are two protein bands with apparent molecular masses of 180 and 40 kDa, that are clearly a with an apparent molecular mass of kDa is also the and proteins, the had no UG binding not that this is an a that the UG-binding of UG monomers to is not although both of these have when and are by C. A. Z. G. and A. B. Mukherjee, UG is a homodimer and both the reduced and UG interact with both the 190- and 49-kDa binding proteins. human cells we have that in these cells only the 190-kDa protein was to UG G. Miele L. Cordella-Miele E. Mukherjee A.B. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). present we that in some tissues (e.g. heart, spleen, and reduced UG binds to both 190- and 49-kDa proteins, while in others (e.g. trachea and binding is detectable only with the 190-kDa in the no binding was the possibility that the 190- and 49-kDa proteins expressed in a to and the and the UG-binding proteins are to these determine whether the expression of the UG-binding proteins is and we treated the NIH 3T3 cells with agents that growth and lipopolysaccharide when these cells treated with and affinity was the of the UG-binding proteins, increased with the Both and are and UG is known to antiinflammatory the apparent of125I-UG binding by these agents the of a to the the of which is by the of UG with its binding clearly when the UG receptor-mediated cellular pathways are in UG potent antiinflammatory and antichemotactic (21Miele L. Cordella-Miele E. Mukherjee A.B. Endocr. Rev. 1987; 8: 474-490Crossref PubMed Scopus (151) Google Scholar, L. Cordella-Miele E. G. A. Mukherjee A.B. J. Endocrinol. Invest. 1994; 17: PubMed Scopus Google Scholar, A.B. N. Z. Am. J. Google Scholar), and we have that it binds to a protein with a molecular mass of 190 kDa present on human cells G. Miele L. Cordella-Miele E. Mukherjee A.B. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). also that the ECM invasion by NIH 3T3 and human cells was by UG pretreatment of these cells G. Miele L. Cordella-Miele E. Mukherjee A.B. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). the present we sought to determine whether reduced UG also had the same effect on the cells and if so, whether such effect was the presence of the UG that in addition to the the reduced UG also suppresses the ECM invasion by NIH 3T3 and human cells not while and reduced UG both the ECM invasion in and cells, it had no such effect on the fibrosarcoma cells protein, had no effect on these cells, and when was used as in the no invasion Most interestingly, the fibrosarcoma cells, in which UG had no effect on ECM invasion, also did not that the effect of UG is of on extracellular matrix of NIH mastocytoma, sarcoma, and fibrosarcoma the of three of and used was the of three of and used was in a the of its UG was to a steroid-inducible secretory protein, the expression of which was to the epithelia (1Krishnan R.S. Daniel Jr., J.C. Science. 1967; 158: 490-492Crossref PubMed Scopus (233) Google Scholar, H.M. Biochim. Biophys. 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