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Glutamate Secretion and Metabotropic Glutamate Receptor 1 Expression during Kaposi's Sarcoma-Associated Herpesvirus Infection Promotes Cell Proliferation


Kaposi's sarcoma associated herpesvirus (KSHV), prevalent in immunosuppressed HIV infected individuals and transplant recipients, is etiologically associated with cancers such as endothelial Kaposi's sarcoma (KS) and B-cell primary effusion lymphoma (PEL). Both KS and PEL develop from the unlimited proliferation of KSHV infected cells. Increased secretion of various host cytokines and growth factors, and the activation of their corresponding receptors, are shown to be contributing to the proliferation of KSHV latently infected cells. Glutamate, a neurotransmitter, is also involved in several cellular events including cell proliferation. In the present study, we report that KSHV-infected latent cells induce the secretion of glutamate and activation of metabotropic glutamate receptor 1 (mGluR1), and KSHV latency associated LANA-1 and Kaposin A proteins are involved in glutaminase and mGluR1 expression. Our functional analysis showed that elevated secretion of glutamate and mGluR1 activation is linked to increased proliferation of KSHV infected cells and glutamate release inhibitor and glutamate receptor antagonists blocked the proliferation of KSHV infected cells. These studies show that proliferation of cancer cells latently infected with KSHV in part depends upon glutamate and glutamate receptor and therefore could potentially be used as therapeutic targets for the control and elimination of KSHV associated cancers.


Vyšlo v časopise: Glutamate Secretion and Metabotropic Glutamate Receptor 1 Expression during Kaposi's Sarcoma-Associated Herpesvirus Infection Promotes Cell Proliferation. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004389
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004389

Souhrn

Kaposi's sarcoma associated herpesvirus (KSHV), prevalent in immunosuppressed HIV infected individuals and transplant recipients, is etiologically associated with cancers such as endothelial Kaposi's sarcoma (KS) and B-cell primary effusion lymphoma (PEL). Both KS and PEL develop from the unlimited proliferation of KSHV infected cells. Increased secretion of various host cytokines and growth factors, and the activation of their corresponding receptors, are shown to be contributing to the proliferation of KSHV latently infected cells. Glutamate, a neurotransmitter, is also involved in several cellular events including cell proliferation. In the present study, we report that KSHV-infected latent cells induce the secretion of glutamate and activation of metabotropic glutamate receptor 1 (mGluR1), and KSHV latency associated LANA-1 and Kaposin A proteins are involved in glutaminase and mGluR1 expression. Our functional analysis showed that elevated secretion of glutamate and mGluR1 activation is linked to increased proliferation of KSHV infected cells and glutamate release inhibitor and glutamate receptor antagonists blocked the proliferation of KSHV infected cells. These studies show that proliferation of cancer cells latently infected with KSHV in part depends upon glutamate and glutamate receptor and therefore could potentially be used as therapeutic targets for the control and elimination of KSHV associated cancers.


Zdroje

1. ChangY, CesarmanE, PessinMS, LeeF, CulpepperJ, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869.

2. CesarmanE, ChangY, MoorePS, SaidJW, KnowlesDM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191.

3. SoulierJ, GrolletL, OksenhendlerE, CacoubP, Cazals-HatemD, et al. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86: 1276–1280.

4. DourmishevLA, DourmishevAL, PalmeriD, SchwartzRA, LukacDM (2003) Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis. Microbiol Mol Biol Rev 67: 175–212 table of contents.

5. GanemD (1998) Human herpesvirus 8 and its role in the genesis of Kaposi's sarcoma. Curr Clin Top Infect Dis 18: 237–251.

6. ZhongW, WangH, HerndierB, GanemD (1996) Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A 93: 6641–6646.

7. KrishnanHH, NaranattPP, SmithMS, ZengL, BloomerC, et al. (2004) Concurrent expression of latent and a limited number of lytic genes with immune modulation and antiapoptotic function by Kaposi's sarcoma-associated herpesvirus early during infection of primary endothelial and fibroblast cells and subsequent decline of lytic gene expression. J Virol 78: 3601–3620.

8. NaranattPP, KrishnanHH, SvojanovskySR, BloomerC, MathurS, et al. (2004) Host gene induction and transcriptional reprogramming in Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8)-infected endothelial, fibroblast, and B cells: insights into modulation events early during infection. Cancer Res 64: 72–84.

9. CaiQ, VermaSC, LuJ, RobertsonES Molecular biology of Kaposi's sarcoma-associated herpesvirus and related oncogenesis. Adv Virus Res 78: 87–142.

10. MesriEA, CesarmanE, BoshoffC Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10: 707–719.

11. WenKW, DamaniaB Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett 289: 140–150.

12. EnsoliB, NakamuraS, SalahuddinSZ, BiberfeldP, LarssonL, et al. (1989) AIDS-Kaposi's sarcoma-derived cells express cytokines with autocrine and paracrine growth effects. Science 243: 223–226.

13. DrexlerHG, MeyerC, GaidanoG, CarboneA (1999) Constitutive cytokine production by primary effusion (body cavity-based) lymphoma-derived cell lines. Leukemia 13: 634–640.

14. OksenhendlerE, CarcelainG, AokiY, BoulangerE, MaillardA, et al. (2000) High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood 96: 2069–2073.

15. AsouH, SaidJW, YangR, MunkerR, ParkDJ, et al. (1998) Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. Blood 91: 2475–2481.

16. EnsoliB, SturzlM (1998) Kaposi's sarcoma: a result of the interplay among inflammatory cytokines, angiogenic factors and viral agents. Cytokine Growth Factor Rev 9: 63–83.

17. XuY, GanemD (2007) Induction of chemokine production by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells. J Gen Virol 88: 46–50.

18. BiberfeldP, EnsoliB, SturzlM, SchulzTF (1998) Kaposi sarcoma-associated herpesvirus/human herpesvirus 8, cytokines, growth factors and HIV in pathogenesis of Kaposi's sarcoma. Curr Opin Infect Dis 11: 97–105.

19. CastiglioneM, CalafioreM, CostaL, SortinoMA, NicolettiF, et al. (2008) Group I metabotropic glutamate receptors control proliferation, survival and differentiation of cultured neural progenitor cells isolated from the subventricular zone of adult mice. Neuropharmacology 55: 560–567.

20. ConnPJ, PinJP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37: 205–237.

21. DingledineR, BorgesK, BowieD, TraynelisSF (1999) The glutamate receptor ion channels. Pharmacol Rev 51: 7–61.

22. MarinYE, NamkoongJ, Cohen-SolalK, ShinSS, MartinoJJ, et al. (2006) Stimulation of oncogenic metabotropic glutamate receptor 1 in melanoma cells activates ERK1/2 via PKCepsilon. Cell Signal 18: 1279–1286.

23. CollardCD, ParkKA, MontaltoMC, AlapatiS, BurasJA, et al. (2002) Neutrophil-derived glutamate regulates vascular endothelial barrier function. J Biol Chem 277: 14801–14811.

24. PachecoR, CiruelaF, CasadoV, MallolJ, GallartT, et al. (2004) Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation. J Biol Chem 279: 33352–33358.

25. SkerryTM, GeneverPG (2001) Glutamate signalling in non-neuronal tissues. Trends Pharmacol Sci 22: 174–181.

26. WangFZ, AkulaSM, PramodNP, ZengL, ChandranB (2001) Human herpesvirus 8 envelope glycoprotein K8.1A interaction with the target cells involves heparan sulfate. J Virol 75: 7517–7527.

27. StaskusKA, ZhongW, GebhardK, HerndierB, WangH, et al. (1997) Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 71: 715–719.

28. JuddeJG, LacosteV, BriereJ, Kassa-KelembhoE, ClytiE, et al. (2000) Monoclonality or oligoclonality of human herpesvirus 8 terminal repeat sequences in Kaposi's sarcoma and other diseases. J Natl Cancer Inst 92: 729–736.

29. AnFQ, FolarinHM, CompitelloN, RothJ, GersonSL, et al. (2006) Long-term-infected telomerase-immortalized endothelial cells: a model for Kaposi's sarcoma-associated herpesvirus latency in vitro and in vivo. J Virol 80: 4833–4846.

30. NunTK, KrollDJ, OberliesNH, SoejartoDD, CaseRJ, et al. (2007) Development of a fluorescence-based assay to screen antiviral drugs against Kaposi's sarcoma associated herpesvirus. Mol Cancer Ther 6: 2360–2370.

31. CurthoysNP, WatfordM (1995) Regulation of glutaminase activity and glutamine metabolism. Annu Rev Nutr 15: 133–159.

32. ShapiroRA, ClarkVM, CurthoysNP (1979) Inactivation of rat renal phosphate-dependent glutaminase with 6-diazo-5-oxo-L-norleucine. Evidence for interaction at the glutamine binding site. J Biol Chem 254: 2835–2838.

33. LiuJ, MartinHJ, LiaoG, HaywardSD (2007) The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. J Virol 81: 10451–10459.

34. GaoP, TchernyshyovI, ChangTC, LeeYS, KitaK, et al. (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458: 762–765.

35. PollockPM, Cohen-SolalK, SoodR, NamkoongJ, MartinoJJ, et al. (2003) Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat Genet 34: 108–112.

36. MartinoJJ, WallBA, MastrantoniE, WilimczykBJ, La CavaSN, et al. Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells. Oncogene

37. SchoenherrCJ, AndersonDJ (1995) Silencing is golden: negative regulation in the control of neuronal gene transcription. Curr Opin Neurobiol 5: 566–571.

38. CrepaldiL, LacknerC, CortiC, FerragutiF (2007) Transcriptional activators and repressors for the neuron-specific expression of a metabotropic glutamate receptor. J Biol Chem 282: 17877–17889.

39. LeeHJ, WallBA, Wangari-TalbotJ, ChenS Regulation of mGluR1 expression in human melanocytes and melanoma cells. Biochim Biophys Acta 1819: 1123–1131.

40. GuardavaccaroD, FrescasD, DorrelloNV, PeschiaroliA, MultaniAS, et al. (2008) Control of chromosome stability by the beta-TrCP-REST-Mad2 axis. Nature 452: 365–369.

41. WestbrookTF, HuG, AngXL, MulliganP, PavlovaNN, et al. (2008) SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 452: 370–374.

42. SadlerR, WuL, ForghaniB, RenneR, ZhongW, et al. (1999) A complex translational program generates multiple novel proteins from the latently expressed kaposin (K12) locus of Kaposi's sarcoma-associated herpesvirus. J Virol 73: 5722–5730.

43. MuralidharS, VeytsmannG, ChandranB, AblashiD, DonigerJ, et al. (2000) Characterization of the human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) oncogene, kaposin (ORF K12). J Clin Virol 16: 203–213.

44. KlicheS, NagelW, KremmerE, AtzlerC, EgeA, et al. (2001) Signaling by human herpesvirus 8 kaposin A through direct membrane recruitment of cytohesin-1. Mol Cell 7: 833–843.

45. MuralidharS, PumferyAM, HassaniM, SadaieMR, KishishitaM, et al. (1998) Identification of kaposin (open reading frame K12) as a human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) transforming gene. J Virol 72: 4980–4988.

46. ChenX, ChengL, JiaX, ZengY, YaoS, et al. (2009) Human immunodeficiency virus type 1 Tat accelerates Kaposi sarcoma-associated herpesvirus Kaposin A-mediated tumorigenesis of transformed fibroblasts in vitro as well as in nude and immunocompetent mice. Neoplasia 11: 1272–1284.

47. YeZC, SontheimerH (1999) Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59: 4383–4391.

48. LyonsSA, ChungWJ, WeaverAK, OgunrinuT, SontheimerH (2007) Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res 67: 9463–9471.

49. SadagopanS, Sharma-WaliaN, VeettilMV, BotteroV, LevineR, et al. (2009) Kaposi's sarcoma-associated herpesvirus upregulates angiogenin during infection of human dermal microvascular endothelial cells, which induces 45S rRNA synthesis, antiapoptosis, cell proliferation, migration, and angiogenesis. J Virol 83: 3342–3364.

50. DanboltNC (2001) Glutamate uptake. Prog Neurobiol 65: 1–105.

51. DerouicheA, RauenT (1995) Coincidence of L-glutamate/L-aspartate transporter (GLAST) and glutamine synthetase (GS) immunoreactions in retinal glia: evidence for coupling of GLAST and GS in transmitter clearance. J Neurosci Res 42: 131–143.

52. RauenT, WiessnerM (2000) Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS. Neurochem Int 37: 179–189.

53. DangCV, LeA, GaoP (2009) MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 15: 6479–6483.

54. MajumderS (2006) REST in good times and bad: roles in tumor suppressor and oncogenic activities. Cell Cycle 5: 1929–1935.

55. MossAC, JacobsonGM, WalkerLE, BlakeNW, MarshallE, et al. (2009) SCG3 transcript in peripheral blood is a prognostic biomarker for REST-deficient small cell lung cancer. Clin Cancer Res 15: 274–283.

56. Gurrola-DiazC, LacroixJ, DihlmannS, BeckerCM, von Knebel DoeberitzM (2003) Reduced expression of the neuron restrictive silencer factor permits transcription of glycine receptor alpha1 subunit in small-cell lung cancer cells. Oncogene 22: 5636–5645.

57. WestbrookTF, MartinES, SchlabachMR, LengY, LiangAC, et al. (2005) A genetic screen for candidate tumor suppressors identifies REST. Cell 121: 837–848.

58. HuangY, MyersSJ, DingledineR (1999) Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nat Neurosci 2: 867–872.

59. NaruseY, AokiT, KojimaT, MoriN (1999) Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes. Proc Natl Acad Sci U S A 96: 13691–13696.

60. KrithivasA, YoungDB, LiaoG, GreeneD, HaywardSD (2000) Human herpesvirus 8 LANA interacts with proteins of the mSin3 corepressor complex and negatively regulates Epstein-Barr virus gene expression in dually infected PEL cells. J Virol 74: 9637–9645.

61. AndresME, BurgerC, Peral-RubioMJ, BattaglioliE, AndersonME, et al. (1999) CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proc Natl Acad Sci U S A 96: 9873–9878.

62. RzeskiW, IkonomidouC, TurskiL (2002) Glutamate antagonists limit tumor growth. Biochem Pharmacol 64: 1195–1200.

63. CavalheiroEA, OlneyJW (2001) Glutamate antagonists: deadly liaisons with cancer. Proc Natl Acad Sci U S A 98: 5947–5948.

64. IwamotoFM, KreislTN, KimL, DuicJP, ButmanJA, et al. Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas. Cancer 116: 1776–1782.

65. YipD, LeMN, ChanJL, LeeJH, MehnertJA, et al. (2009) A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma. Clin Cancer Res 15: 3896–3902.

66. NamkoongJ, ShinSS, LeeHJ, MarinYE, WallBA, et al. (2007) Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma. Cancer Res 67: 2298–2305.

67. Sharma-WaliaN, PaulAG, BotteroV, SadagopanS, VeettilMV, et al. Kaposi's sarcoma associated herpes virus (KSHV) induced COX-2: a key factor in latency, inflammation, angiogenesis, cell survival and invasion. PLoS Pathog 6: e1000777.

68. AkulaSM, PramodNP, WangFZ, ChandranB (2002) Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 108: 407–419.

69. VartRJ, NikitenkoLL, LagosD, TrotterMW, CannonM, et al. (2007) Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res 67: 4042–4051.

70. TiscorniaG, SingerO, VermaIM (2006) Production and purification of lentiviral vectors. Nat Protoc 1: 241–245.

71. ChoiKY, ChangK, PickelJM, BadgerJD2nd, RocheKW Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice. Proc Natl Acad Sci U S A 108: 15219–15224.

72. Valiya VeettilM, SadagopanS, KerurN, ChakrabortyS, ChandranB Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi's sarcoma-associated herpesvirus. PLoS Pathog 6: e1001238.

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