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Reversible upregulation of tropomyosin-related kinase receptor B by geranylgeranoic acid in human neuroblastoma SH-SY5Y cells

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

All-trans retinoic acid (ATRA) plays crucial roles in cell survival and differentiation of neuroblastoma cells. In the present study, we investigated the effects of geranylgeranoic acid (GGA), an acyclic retinoid, on differentiation and tropomyosin-related kinase receptor B (TrkB) gene expression in SH-SY5Y human neuroblastoma cells in comparison with ATRA. GGA induced growth suppression and neural differentiation to the same extent as ATRA. Two variants (145 and 95 kD) of the TrkB protein were dramatically increased by GGA treatment, comparable to the effect of ATRA. Following 6- to 8-day GGA treatment, the effect of GGA on TrkB was reversed after 2–4 days of its removal, whereas the effect of ATRA was irreversible under the same conditions. Both GGA and ATRA upregulated the cellular levels of three major TrkB messenger RNA splice variants in a time-dependent manner. Time-dependent induction of cell cycle-related genes, such as cyclin D1 and retinoblastoma protein, and amplification of the neural progenitor cell marker, brain lipid binding protein, were suppressed by GGA treatment and were completely abolished by ATRA. ATRA and GGA induced retinoic acid receptor β (RARβ) expression, whereas the time-dependent expression of both RARα and RARγ was abolished by ATRA, but not by GGA. Our results suggest that GGA may be able to restore neuronal properties of SH-SY5Y human neuroblastoma cells in a similar but not identical way to ATRA.

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References

  1. Yoshii A, Constantine-Paton M (2010) Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 70:304–322

    PubMed  CAS  Google Scholar 

  2. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309

    Article  PubMed  CAS  Google Scholar 

  3. Middlemas DS, Lindberg RA, Hunter T (1991) trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol 11:143–153

    PubMed  CAS  Google Scholar 

  4. Klein R, Conway D, Parada LF, Barbacid M (1990) The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 61:647–656

    Article  PubMed  CAS  Google Scholar 

  5. Rose CR, Blum R, Pichler B, Lepier A, Kafitz KW, Konnerth A (2003) Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426:74–78

    Article  PubMed  CAS  Google Scholar 

  6. Zuccato C, Marullo M, Conforti P, MacDonald ME, Tartari M, Cattaneo E (2008) Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington’s disease. Brain Pathol 18:225–238

    Article  PubMed  CAS  Google Scholar 

  7. Ruiz-Leon Y, Pascual A (2003) Induction of tyrosine kinase receptor b by retinoic acid allows brain-derived neurotrophic factor-induced amyloid precursor protein gene expression in human SH-SY5Y neuroblastoma cells. Neuroscience 120:1019–1026

    Article  PubMed  CAS  Google Scholar 

  8. Kaplan DR, Matsumoto K, Lucarelli E, Thiele CJ (1993) Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Eukaryotic Signal Transduction Group. Neuron 11:321–331

    Article  PubMed  CAS  Google Scholar 

  9. Hu YQ, Koo PH (1998) Inhibition of phosphorylation of TrkB and TrkC and their signal transduction by alpha2-macroglobulin. J Neurochem 71:213–220

    Article  PubMed  CAS  Google Scholar 

  10. Edsjo A, Lavenius E, Nilsson H, Hoehner JC, Simonsson P, Culp LA, Martinsson T, Larsson C, Pahlman S (2003) Expression of trkB in human neuroblastoma in relation to MYCN expression and retinoic acid treatment. Lab Investig 83:813–823

    PubMed  Google Scholar 

  11. Hecht M, Schulte JH, Eggert A, Wilting J, Schweigerer L (2005) The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness. Carcinogenesis 26:2105–2115

    Article  PubMed  CAS  Google Scholar 

  12. Holback S, Adlerz L, Iverfeldt K (2005) Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells. J Neurochem 95:1059–1068

    Article  PubMed  CAS  Google Scholar 

  13. Kou W, Luchtman D, Song C (2008) Eicosapentaenoic acid (EPA) increases cell viability and expression of neurotrophin receptors in retinoic acid and brain-derived neurotrophic factor differentiated SH-SY5Y cells. Eur J Nutr 47:104–113

    Article  PubMed  CAS  Google Scholar 

  14. Nishida Y, Adati N, Ozawa R, Maeda A, Sakaki Y, Takeda T (2008) Identification and classification of genes regulated by phosphatidylinositol 3-kinase- and TRKB-mediated signalling pathways during neuronal differentiation in two subtypes of the human neuroblastoma cell line SH-SY5Y. BMC Res Notes 1:95

    Article  PubMed  Google Scholar 

  15. Ehrhard PB, Ganter U, Schmutz B, Bauer J, Otten U (1993) Expression of low-affinity NGF receptor and trkB mRNA in human SH-SY5Y neuroblastoma cells. FEBS Lett 330:287–292

    Article  PubMed  CAS  Google Scholar 

  16. Chen CC, Hsu LW, Huang LT, Huang TL (2010) Chronic administration of cyclosporine A changes expression of BDNF and TrkB in rat hippocampus and midbrain. Neurochem Res 35:1098–1104

    Article  PubMed  CAS  Google Scholar 

  17. Muto Y, Moriwaki H, Omori M (1981) In vitro binding affinity of novel synthetic polyprenoids (polyprenoic acids) to cellular retinoid-binding proteins. Gann 72:974–977

    PubMed  CAS  Google Scholar 

  18. Araki H, Shidoji Y, Yamada Y, Moriwaki H, Muto Y (1995) Retinoid agonist activities of synthetic geranylgeranoic acid derivatives. Biochem Biophys Res Commun 209:66–72

    Article  PubMed  CAS  Google Scholar 

  19. Larson RS, Tallman MS (2003) Retinoic acid syndrome: manifestations, pathogenesis, and treatment. Best Pract Res Clin Haematol 16:453–461

    Article  PubMed  CAS  Google Scholar 

  20. Muto Y, Moriwaki H, Saito A (1999) Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 340:1046–1047

    Article  PubMed  CAS  Google Scholar 

  21. Kotti T, Ramirez D, Pfeiffer B, Huber K, Russell D (2006) Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc Natl Acad Sci USA 103:3869–3874

    Article  PubMed  CAS  Google Scholar 

  22. Kotti T, Head DD, McKenna CE, Russell DW (2008) Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation. Proc Natl Acad Sci USA 105:11394–11399

    Article  PubMed  CAS  Google Scholar 

  23. Russell DW, Halford RW, Ramirez DM, Shah R, Kotti T (2009) Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain. Annu Rev Biochem 78:1017–1040

    Article  PubMed  CAS  Google Scholar 

  24. Lu JY, Hofmann SL (2006) Thematic review series: lipid posttranslational modifications. Lysosomal metabolism of lipid-modified proteins. J Lipid Res 47:1352–1357

    Article  PubMed  CAS  Google Scholar 

  25. Shidoji Y, Ogawa H (2004) Natural occurrence of cancer-preventive geranylgeranoic acid in medicinal herbs. J Lipid Res 45:1092–1103

    Article  PubMed  CAS  Google Scholar 

  26. Shi H, Cui H, Alam G, Gunning WT, Nestor A, Giovannucci D, Zhang M, Ding HF (2008) Nestin expression defines both glial and neuronal progenitors in postnatal sympathetic ganglia. J Comp Neurol 508:867–878

    Article  PubMed  CAS  Google Scholar 

  27. Xie HR, Hu LS, Li GY (2010) SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson’s disease. Chin Med J (Engl) 123:1086–1092

    CAS  Google Scholar 

  28. Mita R, Coles JE, Glubrecht DD, Sung R, Sun X, Godbout R (2007) B-FABP-expressing radial glial cells: the malignant glioma cell of origin? Neoplasia 9:734–744

    Article  PubMed  CAS  Google Scholar 

  29. Goto Y, Koyanagi K, Narita N, Kawakami Y, Takata M, Uchiyama A, Nguyen L, Nguyen T, Ye X, Morton DL, Hoon DS (2010) Aberrant fatty acid-binding protein-7 gene expression in cutaneous malignant melanoma. J Investig Dermatol 130:221–229

    Article  PubMed  CAS  Google Scholar 

  30. Nasrollahzadeh J, Siassi F, Doosti M, Eshraghian MR, Shokri F, Modarressi MH, Mohammadi-Asl J, Abdi K, Nikmanesh A, Karimian SM (2008) The influence of feeding linoleic, gamma-linolenic and docosahexaenoic acid rich oils on rat brain tumor fatty acids composition and fatty acid binding protein 7 mRNA expression. Lipids Health Dis 7:45

    Article  PubMed  Google Scholar 

  31. Timmerman SL, Pfingsten JS, Kieft JS, Krushel LA (2008) The 5′ leader of the mRNA encoding the mouse neurotrophin receptor TrkB contains two internal ribosomal entry sites that are differentially regulated. PLoS One 3:e3242

    Article  Google Scholar 

  32. Jamsa A, Hasslund K, Cowburn RF, Backstrom A, Vasange M (2004) The retinoic acid and brain-derived neurotrophic factor differentiated SH-SY5Y cell line as a model for Alzheimer’s disease-like tau phosphorylation. Biochem Biophys Res Commun 319:993–1000

    Article  PubMed  CAS  Google Scholar 

  33. Nitti M, Furfaro AL, Cevasco C, Traverso N, Marinari UM, Pronzato MA, Domenicotti C (2010) PKC delta and NADPH oxidase in retinoic acid-induced neuroblastoma cell differentiation. Cell Signal 22:828–835

    Article  PubMed  CAS  Google Scholar 

  34. Carpentier A, Balitrand N, Rochette-Egly C, Shroot B, Degos L, Chomienne C (1997) Distinct sensitivity of neuroblastoma cells for retinoid receptor agonists: evidence for functional receptor heterodimers. Oncogene 15:1805–1813

    Article  PubMed  CAS  Google Scholar 

  35. Joshi S, Guleria R, Pan J, DiPette D, Singh US (2006) Retinoic acid receptors and tissue-transglutaminase mediate short-term effect of retinoic acid on migration and invasion of neuroblastoma SH-SY5Y cells. Oncogene 25:240–247

    PubMed  CAS  Google Scholar 

  36. Cheung B, Yan J, Smith SA, Nguyen T, Lee M, Kavallaris M, Norris MD, Haber M, Marshall GM (2003) Growth inhibitory retinoid effects after recruitment of retinoid X receptor beta to the retinoic acid receptor beta promoter. Int J Cancer 105:856–867

    Article  PubMed  CAS  Google Scholar 

  37. Yamada Y, Shidoji Y, Fukutomi Y, Ishikawa T, Kaneko T, Nakagama H, Imawari M, Moriwaki H, Muto Y (1994) Positive and negative regulations of albumin gene expression by retinoids in human hepatoma cell lines. Mol Carcinog 10:151–158

    Article  PubMed  CAS  Google Scholar 

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  1. Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Siebold, Nagayo, Nagasaki, 851-2195, Japan

    Chiharu Sakane & Yoshihiro Shidoji

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  1. Chiharu Sakane
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  2. Yoshihiro Shidoji
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Correspondence to Yoshihiro Shidoji.

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Sakane, C., Shidoji, Y. Reversible upregulation of tropomyosin-related kinase receptor B by geranylgeranoic acid in human neuroblastoma SH-SY5Y cells. J Neurooncol 104, 705–713 (2011). https://doi.org/10.1007/s11060-011-0556-y

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  • DOI: https://doi.org/10.1007/s11060-011-0556-y

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