Hepatocyte growth factor (HGF) is involved in the pathogenesis of Kaposi's sarcoma (KS), the most frequent neoplasia in patients with AIDS, characterized by proliferating spindle cells, infiltrating inflammatory cells, angiogenesis, edema, and invasiveness. In vitro, this factor sustains the biological behavior of KS derived cells, after activation of its receptor and the downstream MAPK and AKT signals. In other cell types, namely endothelial and epithelial cells, movement, proliferation, and survival stimulated by HGF and other growth factors and cytokines depend on diacylglycerol kinases (DGK). In an effort to identify new intracellular transducers operative in KS cells, which could represent therapeutic targets, we investigated the role of DGK in KS cell movement and proliferation by treating cells with the DGK pharmacological inhibitor R59949. We report that R59949 strongly inhibits HGF-induced KS motility, proliferation, and anchorage-independent growth with only a partial effect on cell adhesion and spreading. R59949 does not affect cell survival, HGF receptor activation, or the classical MAPK and AKT signalling pathways. Furthermore, we carried out an siRNA screen to characterize the DGK isoforms involved in KS motility and anchorage independent growth. Our data indicate a strong involvement of DGK-δ in KS motility and of DGK-ι in anchorage-independent growth. These results indicate that DGK inhibition is sufficient to impair in vitro KS cell proliferation and movement and suggest that selected DGK represent new pharmacological targets to interfere with the malignant properties of KS, independently from the well-known RAS/MAPK and PI3K/AKT pathways.
Ensoli B, Kaposi's sarcoma: a result of the interplay among inflammatory cytokines, angiogenic factors and viral agents, 10.1016/s1359-6101(97)00037-3
Reitz M. S., Nerurkar L. S., Gallo R. C., Perspective on Kaposi's Sarcoma: Facts, Concepts, and Conjectures, 10.1093/jnci/91.17.1453
Viejo-Borbolla, AIDS Rev, 5, 222 (2003)
Aoki Y., Tosato G., Interactions Between HIV-1 Tat and KSHV, Kaposi Sarcoma Herpesvirus: New Perspectives ISBN:9783540343431 p.309-326, 10.1007/978-3-540-34344-8_12
Sodhi, Cancer Res, 60, 4873 (2000)
Gasperini P., Sakakibara S., Tosato G., Contribution of viral and cellular cytokines to Kaposi's sarcoma-associated herpesvirus pathogenesis, 10.1189/jlb.1107777
Polverini Peter J., Nickoloff Brian J., Role of Scatter Factor and The c-met Protooncogene in the Pathogenesis of Aids-Associated Kaposi's Sarcoma, Advances in Cancer Research (1995) ISBN:9780120066667 p.235-254, 10.1016/s0065-230x(08)60256-0
Maier Jeanette A. M., Mariotti Massimo, Albini Adriana, Comi Paola, Prat Maria, Comoglio Paolo M., Soria Marco R., Over-expression of hepatocyte growth factor in human Kaposi's sarcoma, 10.1002/(sici)1097-0215(19960117)65:2<168::aid-ijc7>3.0.co;2-x
Naidu Y. M., Rosen E. M., Zitnick R., Goldberg I., Park M., Naujokas M., Polverini P. J., Nickoloff B. J., Role of scatter factor in the pathogenesis of AIDS-related Kaposi sarcoma., 10.1073/pnas.91.12.5281
Bussolino F., Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth, 10.1083/jcb.119.3.629
Birchmeier Carmen, Birchmeier Walter, Gherardi Ermanno, Vande Woude George F., Met, metastasis, motility and more, 10.1038/nrm1261
Bardelli Claudio, Sala Marilena, Cavallazzi Umberto, Prat Maria, Agonist Met antibodies define the signalling threshold required for a full mitogenic and invasive program of Kaposi’s Sarcoma cells, 10.1016/j.bbrc.2005.07.020
Lambert Phelps J, Shahrier Aniqa Z, Whitman Audy G, Dyson Ossie F, Reber Adrian J, McCubrey James A, Akula Shaw M, Targeting the PI3K and MAPK pathways to treat Kaposi’s sarcoma-associated herpes virus infection and pathogenesis, 10.1517/14728222.11.5.589
Carrasco Silvia, Mérida Isabel, Diacylglycerol, when simplicity becomes complex, 10.1016/j.tibs.2006.11.004
Sakane Fumio, Imai Shin-ichi, Kai Masahiro, Yasuda Satoshi, Kanoh Hideo, Diacylglycerol kinases: Why so many of them?, 10.1016/j.bbalip.2007.04.006
Topham Matthew K., Prescott Stephen M., Mammalian Diacylglycerol Kinases, a Family of Lipid Kinases with Signaling Functions, 10.1074/jbc.274.17.11447
Cutrupi S., Src-mediated activation of alpha-diacylglycerol kinase is required for hepatocyte growth factor-induced cell motility, 10.1093/emboj/19.17.4614
Baldanzi Gianluca, Mitola Stefania, Cutrupi Santina, Filigheddu Nicoletta, van Blitterswijk Wim J, Sinigaglia Fabiola, Bussolino Federico, Graziani Andrea, Activation of diacylglycerol kinase α is required for VEGF-induced angiogenic signaling in vitro, 10.1038/sj.onc.1207633
Davidson Lindsay, Pawson Adam J., de Maturana Rakel López, Freestone Sarah H., Barran Perdita, Millar Robert P., Maudsley Stuart, Gonadotropin-releasing Hormone-induced Activation of Diacylglycerol Kinase-ζ and Its Association with Active c-Src, 10.1074/jbc.m310784200
Tabellini Giovanna, Billi Anna Maria, Falà Federica, Cappellini Alessandra, Evagelisti Camilla, Manzoli Lucia, Cocco Lucio, Martelli Alberto Maria, Nuclear diacylglycerol kinase-θ is activated in response to nerve growth factor stimulation of PC12 cells, 10.1016/j.cellsig.2004.03.018
Nelson C. D., Perry S. J., Regier D. S., Prescott S. M., Topham M. K., Lefkowitz R. J., Targeting of Diacylglycerol Degradation to M1 Muscarinic Receptors by -Arrestins, 10.1126/science.1134562
Chianale F., Cutrupi S., Rainero E., Baldanzi G., Porporato P. E., Traini S., Filigheddu N., Gnocchi V. F., Santoro M. M., Parolini O., van Blitterswijk W. J., Sinigaglia F., Graziani A., Diacylglycerol Kinase- Mediates Hepatocyte Growth Factor-induced Epithelial Cell Scatter by Regulating Rac Activation and Membrane Ruffling, 10.1091/mbc.e07-02-0177
Bacchiocchi R., Activation of -diacylglycerol kinase is critical for the mitogenic properties of anaplastic lymphoma kinase, 10.1182/blood-2005-01-0316
Regier D. S., Higbee J., Lund K. M., Sakane F., Prescott S. M., Topham M. K., Diacylglycerol kinase regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling, 10.1073/pnas.0500663102
Jiang Ying, Sakane Fumio, Kanoh Hideo, Walsh James P, Selectivity of the diacylglycerol kinase inhibitor 3-{2-(4-[bis-(4-fluorophenyl)methylene]-1-piperidinyl)ethyl}-2,3-dihydro-2-thioxo-4(1H)quinazolinone (R59949) among diacylglycerol kinase subtypes, 10.1016/s0006-2952(99)00395-0
Prat M, Crepaldi T, Gandino L, Giordano S, Longati P, Comoglio P, C-terminal truncated forms of Met, the hepatocyte growth factor receptor., 10.1128/mcb.11.12.5954
Prat, J Cell Sci, 111, 237 (1998)
Siegal Bruno, Levinton-Kriss Sofia, Schiffer Aaron, Sayar Joshua, Engelberg Isaac, Vonsover Ami, Ramon Yochanan, Rubinstein Ethan, Kaposi's sarcoma in immunosuppression possibly the result of a dual viral infection, 10.1002/1097-0142(19900201)65:3<492::aid-cncr2820650320>3.0.co;2-c
de Chaffoy de Courcelles, J Biol Chem, 264, 3274 (1989)
Benelli, Int J Biol Markers, 14, 243 (1999)
Herndier Brian G., Werner Albrecht, Arnstein Paul, Abbey Nancy W., Demartis Francesco, Cohen Robert L., Shuman Marc A., Levy Jay A., Characterization of a human Kaposiʼs sarcoma cell line that induces angiogenic tumors in animals : , 10.1097/00002030-199405000-00002
Prakash O., Human Kaposi's Sarcoma Cell-Mediated Tumorigenesis in Human Immunodeficiency Type 1 Tat-Expressing Transgenic Mice, 10.1093/jnci/92.9.721
Sharma Guru-Dutt, He Jiucheng, Bazan Haydee E. P., p38 and ERK1/2 Coordinate Cellular Migration and Proliferation in Epithelial Wound Healing : EVIDENCE OF CROSS-TALK ACTIVATION BETWEEN MAP KINASE CASCADES, 10.1074/jbc.m302650200
Scarpino Stefania, Stoppacciaro Antonella, Ballerini Francesca, Marchesi Maurizio, Prat Maria, Stella M. Cristina, Sozzani Silvano, Allavena Paola, Mantovani Alberto, Ruco Luigi P., Papillary Carcinoma of the Thyroid, 10.1016/s0002-9440(10)64951-6
Zhang Y.-W., Su Y., Volpert O. V., Woude G. F. V., Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation, 10.1073/pnas.2135113100
Miele Claudia, Paturzo Flora, Teperino Raffaele, Sakane Fumio, Fiory Francesca, Oriente Francesco, Ungaro Paola, Valentino Rossella, Beguinot Francesco, Formisano Pietro, Glucose Regulates Diacylglycerol Intracellular Levels and Protein Kinase C Activity by Modulating Diacylglycerol Kinase Subcellular Localization, 10.1074/jbc.m702481200
Tang Wen, Bunting Michaeline, Zimmerman Guy A., McIntyre Thomas M., Prescott Stephen M., Molecular Cloning of a Novel Human Diacylglycerol Kinase Highly Selective for Arachidonate-containing Substrates, 10.1074/jbc.271.17.10237
Baldanzi G, Alchera E, Imarisio C, Gaggianesi M, Dal Ponte C, Nitti M, Domenicotti C, van Blitterswijk W J, Albano E, Graziani A, Carini R, Negative regulation of diacylglycerol kinase θ mediates adenosine-dependent hepatocyte preconditioning, 10.1038/cdd.2009.210
Bunting, J Biol Chem, 271, 10230 (1996)
Filigheddu, Anticancer Res, 27, 1489 (2007)
Abramovici Hanan, Gee Stephen H., Morphological changes and spatial regulation of diacylglycerol kinase-ζ, syntrophins, and Rac1 during myoblast fusion, 10.1002/cm.20204
Raben Daniel, M., Nuclear diacylglycerol kinases: regulation and roles, 10.2741/2704
Kai Masahiro, Yasuda Satoshi, Imai Shin-ichi, Toyota Minoru, Kanoh Hideo, Sakane Fumio, Diacylglycerol kinase α enhances protein kinase Cζ-dependent phosphorylation at Ser311 of p65/RelA subunit of nuclear factor-κB, 10.1016/j.febslet.2009.09.017
Li D., Urs A. N., Allegood J., Leon A., Merrill A. H., Sewer M. B., Cyclic AMP-Stimulated Interaction between Steroidogenic Factor 1 and Diacylglycerol Kinase Facilitates Induction of CYP17, 10.1128/mcb.00355-07
Crotty T., Cai J., Sakane F., Taketomi A., Prescott S. M., Topham M. K., Diacylglycerol kinase regulates protein kinase C and epidermal growth factor receptor signaling, 10.1073/pnas.0604104103
Flores Ignacio, Casaseca Teresa, Martinez-A Carlos, Kanoh Hideo, Merida Isabel, Phosphatidic Acid Generation through Interleukin 2 (IL-2)-induced -Diacylglycerol Kinase Activation Is an Essential Step in IL-2-mediated Lymphocyte Proliferation, 10.1074/jbc.271.17.10334
Bibliographic reference
Baldanzi, Gianluca ; Pietronave, Stefano ; Locarno, Deborah ; Merlin, Simone ; Porporato, Paolo ; et. al. Diacylglycerol kinases are essential for hepatocyte growth factor-dependent proliferation and motility of Kaposi's sarcoma cells.. In: Cancer Science, Vol. 102, no. 7, p. 1329-1336 (2011)