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Growth Hormone Production and Action in N1E-115 Neuroblastoma Cells

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Abstract

Neuroblastoma cells are undifferentiated cells derived from the neural crest and are commonly used as models for studying neural function. Mouse N1E-115 neuroblastoma cells are derived from cancerous tissue and provide a model for studying the oncogenesis of neural cells. As growth hormone (GH) has been implicated as an autocrine or paracrine involved in neural regulation and in the induction or progression of cancer, the possibility that N1E-115 cells are sites of GH production and GH action was assessed. Using RT-PCR, cultured N1E-115 cells were found to express the mouse GH and GH receptor (GHR) genes. Immunocytochemistry demonstrated that both of the translated proteins (GH and its receptor) were abundantly present in the cytoplasm of these cells and their co-localization was established by confocal cytochemistry. GH action in these cells was determined in cells cultured for 72 h in the presence or absence of 10–6 M or 10–9 M mouse GH, which induced neurite sprouting and increased axon growth. In summary, the expression of GH and its receptor in GH responsive tumor-derived N1E-115 neuroblastoma cells suggests they provide a useful experimental model to assess GH actions in neural function or neural oncogenesis.

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References

  • Åberg, N. D., Brywe, K. G., & Isgaard, J. (2006). Aspects of growth hormone and insulin-like growth factor-1 related to neuroprotection, regeneration, and functional plasticity in the adult brain. Science World Journal, 6, 53–80.

    Google Scholar 

  • Amano, T., Richelson, E., & Niremberg, M. (1972). Neurotransmitter synthesis by neuroblastoma clones. Proceedings of the National Academy of Sciences of the United States of America, 69, 258–263. doi:10.1073/pnas.69.1.258.

    Article  PubMed  CAS  Google Scholar 

  • Barann, M., Göthert, M., Brüss, M., & Bönisch, H. (1999). Inhibition by steroids of [14C]-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT3 receptor of N1E-115 neuroblastoma cells. Naunyn-Schmiedeberg’s Archives of Pharmacology, 360, 234–241. doi:10.1007/s002109900089.

    Article  PubMed  CAS  Google Scholar 

  • Baudet, M. -L., Sanders, E. J., & Harvey, S. (2003). Retinal growth hormone in the chick embryo. Endocrinology, 144, 5459–5468. doi:10.1210/en.2003-0651.

    Article  PubMed  CAS  Google Scholar 

  • Byts, N., Samoylenko, A., Fasshauer, T., Ivanisevic, M., Henninghausen, L., Ehrenreigh, H., et al. (2008). Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin. Cell Death and Differentiation, 15, 783–792. doi:10.1038/cdd.2008.1.

    Article  PubMed  CAS  Google Scholar 

  • Donahue, C. P., Kosik, K., & Shors, T. J. (2006). Growth hormone is produced within the hippocampus where it responds to age, sex and stress. Proceedings of the National Academy of Sciences of the United States of America, 103, 6031–6036. doi:10.1073/pnas.0507776103.

    Article  PubMed  CAS  Google Scholar 

  • Dunlop, M. E., Hill, M. A., & Larkins, R. G. (1988). The influence of insulin and sorbinil on myoinositol uptake in peripheral nerve from normal and diabetic rats and a neuroblastoma cell line (N1E-115). Diabetes Research (Edinburgh, Lothian), 8, 51–57.

    CAS  Google Scholar 

  • Favier, J., Lapointe, S., Maliba, R., & Sirois, M. G. (2007). HIF2 alpha reduces growth rate but promotes angiogenesis in a mouse model of neuroblastoma. BMC Cancer, 7, 139–148. doi:10.1186/1471-2407-7-139.

    Article  PubMed  Google Scholar 

  • Friend, K. E., Khandwala, H. M., Flyvbjerg, A., Hill, H., Li, J., & McCutcheon, I. E. (2001). Growth hormone and insulin-like growth factor-1: effects on the growth of glioma cell lines. Growth Hormone & IGF Research, 11, 84–91. doi:10.1054/ghir.2000.0183.

    Article  CAS  Google Scholar 

  • Gossard, F., Kihi, F., Pelletier, G., Dubois, P. M., & Morel, G. (1987). In situ hybridization to rat brain and pituitary gland of growth hormone cDNA. Neuroscience Letters, 79, 251–256. doi:10.1016/0304-3940(87)90438-1.

    Article  PubMed  CAS  Google Scholar 

  • Harvey, S., & Hull, K. (2003). Neural growth hormone: an update. Journal of Molecular Neuroscience, 20, 1–14. doi:10.1385/JMN:20:1:1.

    Article  PubMed  CAS  Google Scholar 

  • Harvey, S., Hull, K. L., & Fraser, R. A. (1993). Growth hormone: neurocrine and neuroendocrine perspectives. Growth Regulation, 3, 161–171.

    PubMed  CAS  Google Scholar 

  • Hull, K. L., & Harvey, S. (2006). Growth hormone and cancer. In G. V. Sherbet (Ed.), The molecular and cellular pathology of cancer progression and prognosis (pp. 97–138). Trivandrum, India: Research Signpost.

    Google Scholar 

  • Hull, K. L., Sanders, E. J., & Harvey, S. (1995). Synthesis and release of growth hormone binding proteins in tumorous somatolactotrophs. Endocrine, 3, 461–467.

    Article  CAS  Google Scholar 

  • Kaulsay, K. K., Mertani, H. C., Tornell, J., Morel, G., Lee, K. O., & Lobie, P. E. (1999). Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone. Experimental Cell Research, 250, 35–50. doi:10.1006/excr.1999.4492.

    Article  PubMed  CAS  Google Scholar 

  • Kisaalita, W. S., & Bowen, J. M. (1996). Effect of culture age on the susceptibility of differing neuroblastoma cells to retinoid cytotoxicity. Biotechnology and Bioengineering, 50, 580–586. doi:10.1002/(SICI)1097-0290(19960605)50:5<580::AID-BIT13>3.0.CO;2-N.

    Article  PubMed  CAS  Google Scholar 

  • Kisaalita, W. S., & Bowen, J. M. (1997). Effect of medium serum concentration on N1E-115 neuroblastoma membrane potential development. In Vitro Cellular & Developmental Biology Animal, 33, 152–155. doi:10.1007/s11626-997-0133-z.

    Article  CAS  Google Scholar 

  • Kwon, M., Godinho, S. A., Chan d hok, N. S., Ganem, N. J., Azioune, A., Thery, M., et al. (2008). Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes & Development, 22, 2189–2203. doi:10.1101/gad.1700908.

    Article  CAS  Google Scholar 

  • Lyuh, E., Kim, H. J., Kim, M., Lee, J. K., Park, K. S., Yoo, K. Y., et al. (2007). Dose-specific or dose-dependent effect of growth hormone treatment on the proliferation and differentiation of culture neuronal cells. Growth Hormone & IGF Research, 17, 315–322. doi:10.1016/j.ghir.2007.03.002.

    Article  CAS  Google Scholar 

  • Marler, K. J., Kozma, R., Ahmed, S., Dong, J. M., Hall, C., & Lim, L. (2005). Outgrowth of neurites from N1E-115 neuroblastoma cells is prevented on repulsive substrates through the action of PAK. Molecular and Cellular Biology, 12, 5226–5241. doi:10.1128/MCB.25.12.5226-5241.2005.

    Article  Google Scholar 

  • Martinoli, M. G., Oullet, J., Rhlaume, E., & Pelletier, G. (1991). Growth hormone and somatostatin gene expression in adult and aging rats as measured by quantitative in situ hybridization. Neuroendocrinology, 54, 607–615. doi:10.1159/000125967.

    Article  PubMed  CAS  Google Scholar 

  • McKinney, M., & Barrett, R. W. (1989). Biochemical evidence for somatostatin receptors in murine neuroblastoma clone N1E-115. European Journal of Pharmacology, 162, 397–405. doi:10.1016/0014-2999(89)90330-0.

    Article  PubMed  CAS  Google Scholar 

  • Möderscheim, T. A. E., Christophidis, L. J., Williams, C. E., & Scheepens, A. (2007). Distinct neuronal growth hormone receptor ligand specificity in the rat brain. Brain Research, 1137, 29–34. doi:10.1016/j.brainres.2006.12.040.

    Article  PubMed  Google Scholar 

  • Mukhina, S., Mertaini, H. C., Guo, K., Lee, K. O., Gluckman, P. D., & Lobie, P. E. (2004). Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proceedings of the National Academy of Sciences of the United States of America, 101, 15166–15171. doi:10.1073/pnas.0405881101.

    Article  PubMed  CAS  Google Scholar 

  • Mummery, C. L., van den Brink, C. E., van der Saag, P. T., & de Laat, S. W. (2005). A short-term screening test for teratogens using differentiating neuroblastoma cells in vitro. Experimental Teratology, 29, 271–279. doi:10.1002/tera.1420290213.

    Article  Google Scholar 

  • Nyberg, F. (2000). Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance. Frontiers in Neuroendocrinology, 21, 330–348. doi:10.1006/frne.2000.0200.

    Article  PubMed  CAS  Google Scholar 

  • Nyberg, F., & Burman, P. (1996). Growth hormone and its receptors in the central nervous system-location and functional significance. Hormone Research, 45, 18–22. doi:10.1159/000184753.

    Article  PubMed  CAS  Google Scholar 

  • Ostlund, P., Lindegren, H., Pettersson, C., & Bedecs, K. (2001). Altered insulin receptor processing and function in scrapie-infected neuroblastoma cell lines. Brain Research Molecular Brain Research, 97, 161–170. doi:10.1016/S0169-328X(01)00316-3.

    Article  PubMed  CAS  Google Scholar 

  • Pandey, V., Perry, J. K., Mohankumar, K. M., Kong, X. J., Liu, S. M., Wu, Z. S., et al. (2008). Autocrine human growth hormone stimulates oncogenicity of endometrial carcinoma cells. Endocrinology, 149, 3909–3919. doi:10.1210/en.2008-0286.

    Article  PubMed  CAS  Google Scholar 

  • Pang, P. K., Wang, R., Shan, J., Karpinski, E., & Benishin, C. G. (1990). Specific inhibition of long-lasting, L-type calcium channels by synthetic parathyroid hormone. Proceedings of the National Academy of Sciences of the United States of America, 87, 623–627. doi:10.1073/pnas.87.2.623.

    Article  PubMed  CAS  Google Scholar 

  • Parsons, S. A., Banks, G. B., Rowland, J. A., Coschigano, K. T., Kopchick, J. J., Waters, M. J., et al. (2003). Genetic disruption of the growth hormone receptor does not influence motoneuron survival in the developing mouse. The International Journal of Developmental Biology, 47, 41–49.

    PubMed  CAS  Google Scholar 

  • Perry, J. K., Emerald, B. S., Mertani, H. C., & Lobie, P. E. (2006). The oncogenic potential of growth hormone. Growth Hormone & IGF Research, 16, 277–289. doi:10.1016/j.ghir.2006.09.006.

    Article  CAS  Google Scholar 

  • Prasad, K. N. (1991). Differentiation of neuroblastoma cells: a useful model for neurobiology and cancer. Biological Reviews of the Cambridge Philosophical Society, 66, 431–451. doi:10.1111/j.1469-185X.1991.tb01148.x.

    Article  PubMed  CAS  Google Scholar 

  • Render, C. L., Hull, K. L., & Harvey, S. (1995). Neural expression of the pituitary GH gene. The Journal of Endocrinology, 147, 413–422. doi:10.1677/joe.0.1470413.

    Article  PubMed  CAS  Google Scholar 

  • Rodrigues, J. M., Luis, A. L., Lobato, J. V., Pinto, M. V., Lopes, M. A., Freitas, M., et al. (2005). Determination of the intracellular Ca2+ concentration in the N1E-115 neuronal cell gene in perspective of its use for peripheric nerve regeneration. Bio-Medical Materials and Engineering, 6, 455–465.

    Google Scholar 

  • Russell, J. W., Windebank, A. J., McNive, M. A., Brat, D. J., & Brimijoin, W. S. (1995). Effect of cisplatin and ACTH4–9 on neural transport in cisplatin induced neurotoxicity. Brain Research, 676, 258–267. doi:10.1016/0006-8993(95)00100-5.

    Article  PubMed  CAS  Google Scholar 

  • Sanders, E. J., Parker, E., Arámburo, C., & Harvey, S. (2005). Retinal growth hormone is an anti-apoptotic factor in embryonic retinal ganglion cell differentiation. Experimental Eye Research, 81, 551–560. doi:10.1016/j.exer.2005.03.013.

    Article  PubMed  CAS  Google Scholar 

  • Sanders, E. J., Parker, E., & Harvey, S. (2008). Growth hormone-mediated survival of embryonic retinal ganglion cells: signaling mechanisms. General and Comparative Endocrinology, 156, 613–621. doi:10.1016/j.ygcen.2008.02.005.

    Article  PubMed  CAS  Google Scholar 

  • Scheepens, A., Möderscheim, T. A., & Gluckman, P. D. (2005). The role of growth hormone in neural development. Hormone Research, 64, 66–72. doi:10.1159/000089320.

    Article  PubMed  CAS  Google Scholar 

  • Schelman, W. R., Andreas, R., Feguson, P., Orr, B., Kang, E., & Weyhenmeyer, J. A. (2004). Angiotensin II attenuates NMDA receptor-mediated neuronal cell death and prevents the associated reduction in bcl-2 expression. Brain Research. Molecular Brain Research, 128, 20–29. doi:10.1016/j.molbrainres.2004.06.001.

    Article  PubMed  CAS  Google Scholar 

  • Schwarz, P. M., Gierten, B., Biossel, J. P., & Förstermann, U. (1998). Expressional down-regulation of neuronal-type nitric oxide synthase I by glucocorticoids in N1E-115 neuroblastoma cells. Molecular Pharmacology, 54, 258–263.

    PubMed  CAS  Google Scholar 

  • Scott, H. J., Stebbing, M. J., Walters, C. E., McLenachan, S., Ransome, M. I., Nichols, N. R., et al. (2006). Differential effects of SOGS2 on neuronal differentiation and morphology. Brain Research, 1067, 138–145. doi:10.1016/j.brainres.2005.10.032.

    Article  PubMed  CAS  Google Scholar 

  • Shastry, P., Basu, A., & Rajadhyaksha, M. S. (2001). Neuroblastoma cell lines—a versatile in vitro model in neurobiology. The International Journal of Neuroscience, 108, 109–126. doi:10.3109/00207450108986509.

    Article  PubMed  CAS  Google Scholar 

  • Sun, L. Y., Evans, M. S., Hsieh, J., Panici, J., & Bathe, A. (2005a). Increased neurogenesis in the dentate gyrus of long-lived Ames dwarf mice. Endocrinology, 146, 1138–1144. doi:10.1210/en.2004-1115.

    Article  PubMed  CAS  Google Scholar 

  • Sun, L. Y., Al-Regaiey, K., Maternak, M. M., Wang, J., & Bartke, A. (2005b). Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiology of Aging, 26, 929–937. doi:10.1016/j.neurobiolaging.2004.07.010.

    Article  PubMed  CAS  Google Scholar 

  • Thiele, C. J. (1999). Neuroblastoma cell lines. In J. Masters (Ed.), Human cell culture (pp. 21–53). Lancaster, UK: Kluwer Academic Publishers.

    Google Scholar 

  • Turnley, A. M. (2005). Growth hormone and SOCS2 regulation of neuronal differentiation: possible role in mental function. Pediatric Endocrinology Reviews, 2, 366–371.

    PubMed  Google Scholar 

  • Turnley, A. M., Faux, C. H., Rietze, R. L., Coonan, J. R., & Bartlett, P. F. (2002). Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling. Nature Neuroscience, 5, 1155–1162. doi:10.1038/nn954.

    Article  PubMed  CAS  Google Scholar 

  • Waters, M. J., & Barclay, J. L. (2007). Does growth hormone drive breast and other cancers. Endocrinology, 148, 4533–4535. doi:10.1210/en.2007-0855.

    Article  PubMed  CAS  Google Scholar 

  • Xu, X. Q., Emerald, B. S., Goh, E. L., Kannan, N., Miller, L. D., Gluckman, P. D., et al. (2005). Gene expression profiling to identify oncogenic determinants of autocrine human growth hormone in human mammary carcinoma. The Journal of Biological Chemistry, 280, 23987–24003. doi:10.1074/jbc.M503869200.

    Article  PubMed  CAS  Google Scholar 

  • Yoshizato, H., Fujikawa, T., Soya, H., Tanada, M., & Nakashima, K. (1998). The growth hormone (GH) gene is expressed in the lateral hypothalamus: enhancement by GH releasing hormone and repression by rest and stress. Endocrinology, 39+, 2545–2551.

    Article  Google Scholar 

  • Yoshizato, H., Fujikawa, T., Shibata, M., Tanada, M., & Nakashima, K. (1999). Stimulation of growth hormone gene expression in the pituitary and brain by panaxginseng CA Meyer. Endocrine Journal, 4(suppl), 858–588.

    Google Scholar 

  • Zhu, T., Starling-Emerald, B., Zhang, X., Lee, K. O., Gluckman, P. D., Mertani, H. C., et al. (2005). Oncogenic transformation of human mammary epithelial cells by autocrine human growth hormone. Cancer Research, 65, 317–324.

    PubMed  CAS  Google Scholar 

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Acknowledgements

Supported by the Natural Science and Engineering Research Council (NSERC) of Canada and by studentships from NSERC and the Alberta Heritage Foundation for Medical Research to CG and BM.

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Correspondence to Steve Harvey.

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Grimbly, C., Martin, B., Karpinski, E. et al. Growth Hormone Production and Action in N1E-115 Neuroblastoma Cells. J Mol Neurosci 39, 117–124 (2009). https://doi.org/10.1007/s12031-009-9194-7

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