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Brain-derived neurotrophic factor induces proliferation, migration, and VEGF secretion in human multiple myeloma cells via activation of MEK-ERK and PI3K/AKT signaling

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Tumor Biology

Abstract

This study investigated the signaling pathways involved in the different biological effects of brain-derived neurotrophic factor (BDNF) in multiple myeloma (MM). The effects of BDNF on proliferation of MM cell lines and primary myeloma cells were examined by [3H]thymidine incorporation assay. The effects of BDNF on MM cells migration were studied by transwell migration assay. Stimulation by BDNF of vascular endothelial growth factor (VEGF) production was analyzed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. The signal-transduction pathways that are activated in response to BDNF were determined by Western blots. VEGF is induced by BDNF in a dose-dependent manner in MM cells. Stimulation of MM cells with BDNF led to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the MEK-extracellular signal-regulated protein kinase pathways. Using specific signal-transduction inhibitors, we demonstrated that MEK is required for BDNF-induced proliferation, whereas activation of PI3K is required for BDNF-stimulated migration and VEGF production. BDNF affects different cell signaling pathways mediating growth, migration, and VEGF secretion in MM cells. Our observations provided the framework for novel therapeutic strategies targeting BDNF signaling cascades in MM.

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References

  1. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002;2:175–87.

    Article  CAS  PubMed  Google Scholar 

  2. Sirohi B, Powles R. Multiple myeloma. Lancet. 2004;363:875–87.

    Article  PubMed  Google Scholar 

  3. Menu E, Asosingh K, Van Riet I, Croucher P, Van Camp B, Vanderkerken K. Myeloma cells (5TMM) and their interactions with the marrow microenvironment. Blood Cells Mol Dis. 2004;33:111–9.

    Article  PubMed  Google Scholar 

  4. Munshi N-C, Wilson C. Increased bone marrow microvessel density in newly diagnosed multiple myeloma carries a poor prognosis. Semin Oncol. 2001;28:565–9.

    Article  CAS  PubMed  Google Scholar 

  5. Vacca A, Ribatti D, Roccaro A-M, Frigeri A, Dammacco F. Bone marrow angiogenesis in patients with active multiple myeloma. Semin Oncol. 2001;28:543–50.

    Article  CAS  PubMed  Google Scholar 

  6. Miller FD, Kaplan DR. Neurotrophin signaling pathways regulating neuronal apoptosis. Cell Mol Life Sci. 2001;58:1045–53.

    Article  CAS  PubMed  Google Scholar 

  7. Donovan MJ, Lin MI, Wiegn P, Ringstedt T, Kraemer R, Hahn R, et al. Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization. Development. 2000;127:4531–40.

    CAS  PubMed  Google Scholar 

  8. Kermani P, Hempstead B. Brain-derived neurotrophic factor: a newly described mediator of angiogenesis. Trends Cardiovasc Med. 2007;17:140–3.

    Article  CAS  PubMed  Google Scholar 

  9. Sun CY, Hu Y, Wu T, Wang YD, He WJ. Effect of brain-derived neurotrophic factor in human myeloma cells on angiogenesis. Zhonghua Xue Ye Xue Za Zhi. 2005;26:602–6 (Chinese).

    CAS  Google Scholar 

  10. Pearse RN, Swendeman SL, Li Y, Rafii D, Hempstead BL. A neurotrophin axis in myeloma: TrkB and BDNF promote tumor cell survival. Blood. 2005;105:4429–36.

    Article  CAS  PubMed  Google Scholar 

  11. Matsumoto L, Wada RK, Yamashiro JM, Kaplan DR, Thiele CJ. Expression of brain-derived neurotrophic factor and p145trkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res. 1995;55:1798–806.

    CAS  PubMed  Google Scholar 

  12. Kowalski PJ, Paulino AF. Perineural invasion in adenoid cystic carcinoma: Its causation/promotion by brain-derived neurotrophic factor. Hum Pathol. 2002;33:933–6.

    Article  CAS  PubMed  Google Scholar 

  13. Satoh F, Mimata H, Nomura T, Fujita Y, Shin T, Sakamoto S, et al. Autocrine expression of neurotrophins and their receptors in prostate cancer. Int J Urol. 2001;8:S28–34.

    Article  CAS  PubMed  Google Scholar 

  14. Jaboin J, Kim CJ, Kaplan DR, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3′-kinase pathway. Cancer Res. 2002;62:6756–63.

    CAS  PubMed  Google Scholar 

  15. Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature. 2004;430:1034–9.

    Article  CAS  PubMed  Google Scholar 

  16. Hu Y, Sun CY, Wang HF, Guo T, Wei WN, Wang YD, et al. Brain-derived neurotrophic factor promotes growth and migration of multiple myeloma cells. Cancer Genet Cytogenet. 2006;169:12–20.

    Article  CAS  PubMed  Google Scholar 

  17. Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM. Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol. 1994;14:759–67.

    CAS  PubMed  Google Scholar 

  18. Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol. 2000;10:381–91.

    Article  CAS  PubMed  Google Scholar 

  19. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 1999;286:1358–62.

    Article  CAS  PubMed  Google Scholar 

  20. Li Z, Zhang J, Liu Z, Woo CW, Thiele CJ. Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death. Cell Death Differ. 2007;14:318–26.

    Article  PubMed  Google Scholar 

  21. Ho R, Eggert A, Hishiki T, Minturn JE, Ikegaki N, Foster P, et al. Resistance to chemotherapy mediated by TrkB in neuroblastomas. Cancer Res. 2002;62:6462–6.

    CAS  PubMed  Google Scholar 

  22. Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R, et al. Expression of VEGF and its receptors by myeloma cells. Leukemia. 2003;17:2025–31.

    Article  CAS  PubMed  Google Scholar 

  23. Lentzsch S, Gries M, Janz M, Bargou R, Dorken B, Mapara MY. Macrophage inflammatory protein 1-alpha (MIP-1α) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood. 2003;101:3568–73.

    Article  CAS  PubMed  Google Scholar 

  24. Tai YT, Podar K, Catley L, Tseng YH, Akiyama M, Shringarpure R, et al. Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3′-kinase/AKT signaling. Cancer Res. 2003;63:5850–8.

    CAS  PubMed  Google Scholar 

  25. Tai YT, Podar K, Mitsiades N, Lin B, Mitsiades C, Gupta D, et al. CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-κB signaling. Blood. 2003;101:2762–9.

    Article  CAS  PubMed  Google Scholar 

  26. Qiang YW, Kopantzev E, Rudikoff S. Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk. Blood. 2002;99:4138–46.

    Article  CAS  PubMed  Google Scholar 

  27. Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res. 2006;66:4249–55.

    Article  CAS  PubMed  Google Scholar 

  28. Anderson KC, Hamblin TJ, Traynor A. Management of multiple myeloma today. Semin Hematol. 1999;36:3–8.

    CAS  PubMed  Google Scholar 

  29. Eleutherakis-Papaiakovou V, Karali M, Kokkonouzis I, Tiliakos I, Dimopoulos MA. Bone marrow angiogenesis and progression in multiple myeloma: clinical significance and therapeutic approach. Leuk Lymphoma. 2003;44:937–48.

    Article  CAS  PubMed  Google Scholar 

  30. Wagner N, Wagner KD, Sefton M, Rodriguez-Tebar A, Grantyn R. An abnormal response of retinoblastoma cells (Y-79) to neurotrophins. Invest Ophthalmol Vis Sci. 2000;41:1932–9.

    CAS  PubMed  Google Scholar 

  31. Yang ZF, Ho DW, Lam CT, Luk JM, Lum CT, Yu WC, et al. Identification of brain-derived neurotrophic factor as a novel functional protein in hepatocellular carcinoma. Cancer Res. 2005;65:219–25.

    CAS  PubMed  Google Scholar 

  32. Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood. 2001;98:428–35.

    Article  CAS  PubMed  Google Scholar 

  33. Pawson T, Nash P. Protein-protein interactions define specificity in signal transduction. Genes Dev. 2000;14:1027–47.

    CAS  PubMed  Google Scholar 

  34. Pawson T, Gish GD, Nash P. SH2 domains interaction modules and cellular wiring. Trends Cell Biol. 2001;11:504–11.

    Article  CAS  PubMed  Google Scholar 

  35. Derksen PW, de Gorter DJ, Meijer HP, Bende RJ, van Dijk M, Lokhorst HM, et al. The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. Leukemia. 2003;17:764–74.

    Article  CAS  PubMed  Google Scholar 

  36. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM, et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood. 2007;109:2708–17.

    CAS  PubMed  Google Scholar 

  37. Hideshima T, Nakamura N, Chauhan D, Anderson KC. Biologic sequelae of interleukin-6 induced PI3-K/AKT signaling in multiple myeloma. Oncogene. 2001;20:5991–6000.

    Article  CAS  PubMed  Google Scholar 

  38. Tu Y, Gardner A, Lichtenstein A. The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. Cancer Res. 2000;60:6763–70.

    CAS  PubMed  Google Scholar 

  39. Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL, et al. Interleukin-6 triggers cell growth via the ras-dependent mitogen-activated protein kinase cascade. J Immunol. 1997;159:2212–21.

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Prof. Tang-chun Wu (Institute of Occupational Medicine, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China) for offering relevant experimental facilities and technical support.

Funding

This work was supported by National Natural Sciences Foundation of People's Republic of China (No. 30670896, for Y.H.; No. 30700331, for C.Y.S.).

Conflict of interest

None.

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Authors and Affiliations

  1. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Dadao, Wuhan, 430022, People’s Republic of China

    Chun-yan Sun, Yu Hu, Jing Huang, Zhang-bo Chu, Lu Zhang, Xiao-mei She & Lei Chen

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  1. Chun-yan Sun
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  2. Yu Hu
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  3. Jing Huang
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Correspondence to Yu Hu.

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Sun, Cy., Hu, Y., Huang, J. et al. Brain-derived neurotrophic factor induces proliferation, migration, and VEGF secretion in human multiple myeloma cells via activation of MEK-ERK and PI3K/AKT signaling. Tumor Biol. 31, 121–128 (2010). https://doi.org/10.1007/s13277-010-0016-x

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  • DOI: https://doi.org/10.1007/s13277-010-0016-x

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