Skip to main content

Advertisement

SpringerLink
Log in

Geranylgeranyltransferase I regulates HIF-1α promoting glioblastoma cell migration and invasion

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Glioblastoma multiforme is a highly migratory and invasive brain tumor in which hypoxia inducible factor-1α (HIF-1α) plays important roles. However, the underlying mechanisms regulating the action of HIF-1α in glioma cell migration and invasion ability remain unclear. We reported here that HIF-1α was regulated by geranylgeranyltransferase I (GGTI), a protein prenylation transferase, and then promoted glioma cell migration and invasion. The migratory and invasive ability of glioma cells were enhanced by hypoxia treatment but inhibited by down-regulation of HIF-1α. GGTI activity inhibition or GGTI specific β subunit (GGTI β) knocking-down decreased HIF-1α protein level. In addition, down-regulation of GGTI β inhibited migration and invasion of glioma cells under hypoxia, while GGTI β over-expression promoted it. Furthermore, the effect of GGTI β over-expression on cell migration and invasion was abolished by HIF-1α down-regulation. In summary, our study showed, for the first time, that HIF-1α was regulated by protein prenylation transferase GGTI and mediated the effect of GGTI on glioma cell migration and invasion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

GGTI:

Geranylgeranyltransferase I

HIF-1α:

Hypoxia inducible factor-1 α

ECM:

Extracellular matrix

FT:

Farnesyltransferase

References

  1. Clarke J, Butowski N, Chang S (2010) Recent advances in therapy for glioblastoma. Arch Neurol 67:279–283

    Article  PubMed  Google Scholar 

  2. Meyer MA (2008) Malignant gliomas in adults. N Engl J Med 359:1850 (author reply 1850)

    Google Scholar 

  3. Minniti G, De Sanctis V, Muni R, Filippone F, Bozzao A, Valeriani M, Osti MF, De Paula U, Lanzetta G, Tombolini V, Maurizi Enrici R (2008) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol 88:97–103

    Article  PubMed  CAS  Google Scholar 

  4. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410

    Article  PubMed  CAS  Google Scholar 

  5. Vordermark D (2005) Significance of hypoxia in malignant glioma. Re: Evans et al. Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res 2004;10:8177–8184; Clin Cancer Res 11:3966–3967 (author reply 3967–3968)

    Google Scholar 

  6. Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG (2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 7:134–153

    Article  PubMed  CAS  Google Scholar 

  7. Kessler J, Hahnel A, Wichmann H, Rot S, Kappler M, Bache M, Vordermark D (2010) HIF-1alpha inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression. BMC Cancer 10:605

    Article  PubMed  CAS  Google Scholar 

  8. Tao BB, Zhang CC, Liu SY, Zhu YC (2012) Involvement of HIF-1 in the migration-promoting effects of hydrogen sulfide in vascular endothelial cells under normoxic conditions. Sheng Li Xue Bao 64:129–134

    PubMed  CAS  Google Scholar 

  9. Jans J, van Dijk JH, van Schelven S, van der Groep P, Willems SH, Jonges TN, van Diest PJ, Bosch JL (2010) Expression and localization of hypoxia proteins in prostate cancer: prognostic implications after radical prostatectomy. Urology 75:786–792

    Article  PubMed  Google Scholar 

  10. Schwab LP, Peacock DL, Majumdar D, Ingels JF, Jensen LC, Smith KD, Cushing RC, Seagroves TN (2012) Hypoxia-inducible factor 1alpha promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res 14:R6

    Article  PubMed  CAS  Google Scholar 

  11. Wong CC, Zhang H, Gilkes DM, Chen J, Wei H, Chaturvedi P, Hubbi ME, Semenza GL (2012) Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J Mol Med (Berl) 90(7):803–815. doi:10.1007/s00109-011-0855-y

    Article  CAS  Google Scholar 

  12. Dai S, Huang ML, Hsu CY, Chao KS (2003) Inhibition of hypoxia inducible factor 1alpha causes oxygen-independent cytotoxicity and induces p53 independent apoptosis in glioblastoma cells. Int J Radiat Oncol Biol Phys 55:1027–1036

    Article  PubMed  CAS  Google Scholar 

  13. Lu H, Li Y, Shu M, Tang J, Huang Y, Zhou Y, Liang Y, Yan G (2009) Hypoxia-inducible factor-1alpha blocks differentiation of malignant gliomas. FEBS J 276:7291–7304

    Article  PubMed  CAS  Google Scholar 

  14. Gillespie DL, Flynn JR, Ragel BT, Arce-Larreta M, Kelly DA, Tripp SR, Jensen RL (2009) Silencing of HIF-1alpha by RNA interference in human glioma cells in vitro and in vivo. Methods Mol Biol 487:283–301

    PubMed  CAS  Google Scholar 

  15. Reymond N, Riou P, Ridley AJ (2012) Rho GTPases and cancer cell transendothelial migration. Methods Mol Biol 827:123–142

    Article  PubMed  CAS  Google Scholar 

  16. Khalil BD, El-Sibai M (2012) Rho GTPases in primary brain tumor malignancy and invasion. J Neurooncol 108(3):333–339. doi:10.1007/s11060-012-0866-8

    Article  PubMed  CAS  Google Scholar 

  17. Zhou J, Li K, Gu Y, Feng B, Ren G, Zhang L, Wang Y, Nie Y, Fan D (2011) Transcriptional up-regulation of RhoE by hypoxia-inducible factor (HIF)-1 promotes epithelial to mesenchymal transition of gastric cancer cells during hypoxia. Biochem Biophys Res Commun 415:348–354

    Article  PubMed  CAS  Google Scholar 

  18. Xue Y, Li NL, Yang JY, Chen Y, Yang LL, Liu WC (2011) Phosphatidylinositol 3′-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1(alpha) and vascular endothelial growth factor expression. Am J Physiol Heart Circ Physiol 300:H2169–H2176

    Article  PubMed  CAS  Google Scholar 

  19. Zhang P, Zhang X, Hao X, Wang Y, Hui Y, Wang H, Hu D, Zhou J (2009) Rac1 activates HIF-1 in retinal pigment epithelium cells under hypoxia. Graefes Arch Clin Exp Ophthalmol 247:633–639

    Article  PubMed  CAS  Google Scholar 

  20. Waheed F, Speight P, Dan Q, Garcia-Mata R, Szaszi K (2012) Affinity precipitation of active Rho-GEFs using a GST-tagged mutant Rho protein (GST-RhoA(G17A)) from epithelial cell lysates. J Vis Exp. doi:10.3791/3932

  21. Zhou XP, Wu KY, Liang B, Fu XQ, Luo ZG (2008) TrkB-mediated activation of geranylgeranyltransferase I promotes dendritic morphogenesis. Proc Natl Acad Sci USA 105:17181–17186

    Article  PubMed  CAS  Google Scholar 

  22. Luo ZG, Je HS, Wang Q, Yang F, Dobbins GC, Yang ZH, Xiong WC, Lu B, Mei L (2003) Implication of geranylgeranyltransferase I in synapse formation. Neuron 40:703–717

    Article  PubMed  CAS  Google Scholar 

  23. Berndt N, Hamilton AD, Sebti SM (2011) Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11:775–791

    Article  PubMed  CAS  Google Scholar 

  24. Ghavami S, Mutawe MM, Schaafsma D, Yeganeh B, Unruh H, Klonisch T, Halayko AJ (2012) Geranylgeranyl transferase 1 modulates autophagy and apoptosis in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 302:L420–L428

    Article  PubMed  CAS  Google Scholar 

  25. Lu J, Chan L, Fiji HD, Dahl R, Kwon O, Tamanoi F (2009) In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I. Mol Cancer Ther 8:1218–1226

    Article  PubMed  CAS  Google Scholar 

  26. Zhou X, Hua L, Zhang W, Zhu M, Shi Q, Li F, Zhang L, Song C, Yu R (2012) FRK controls migration and invasion of human glioma cells by regulating JNK/c-Jun signaling. J Neurooncol 110:9–19

    Article  PubMed  CAS  Google Scholar 

  27. Zhou X, Xu X, Meng Q, Hu J, Zhi T, Shi Q, Yu R (2012) Bex2 is critical for migration and invasion in malignant glioma cells. J Mol Neurosci. doi:10.1007/s12031-012-9864-8

  28. Zhou X, Ma L, Li J, Gu J, Shi Q, Yu R (2012) Effects of SEMA3G on migration and invasion of glioma cells. Oncol Rep 28:269–275

    PubMed  CAS  Google Scholar 

  29. Tremblay P, Beaudet MJ, Tremblay E, Rueda N, Thomas T, Vallieres L (2011) Matrix metalloproteinase 2 attenuates brain tumour growth, while promoting macrophage recruitment and vascular repair. J Pathol 224:222–233

    Article  PubMed  CAS  Google Scholar 

  30. Koul D, Parthasarathy R, Shen R, Davies MA, Jasser SA, Chintala SK, Rao JS, Sun Y, Benvenisite EN, Liu TJ, Yung WK (2001) Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 20:6669–6678

    Article  PubMed  CAS  Google Scholar 

  31. Turcotte S, Desrosiers RR, Beliveau R (2003) HIF-1alpha mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma. J Cell Sci 116:2247–2260

    Article  PubMed  CAS  Google Scholar 

  32. Wu KY, Zhou XP, Luo ZG (2010) Geranylgeranyltransferase I is essential for dendritic development of cerebellar Purkinje cells. Mol Brain 3:18

    Article  PubMed  Google Scholar 

  33. Chen JK, Hu LJ, Wang J, Lamborn KR, Kong EL, Deen DF (2005) Hypoxia-induced BAX overexpression and radiation killing of hypoxic glioblastoma cells. Radiat Res 163:644–653

    Article  PubMed  CAS  Google Scholar 

  34. Advani SH (2010) Targeting mTOR pathway: a new concept in cancer therapy. Indian J Med Paediatr Oncol 31:132–136

    Article  PubMed  CAS  Google Scholar 

  35. Yuan G, Nanduri J, Khan S, Semenza GL, Prabhakar NR (2008) Induction of HIF-1alpha expression by intermittent hypoxia: involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol 217:674–685

    Article  PubMed  CAS  Google Scholar 

  36. Koh MY, Spivak-Kroizman TR, Powis G (2010) HIF-1alpha and cancer therapy. Recent Results Cancer Res 180:15–34

    Article  PubMed  CAS  Google Scholar 

  37. Kim JW, Gao P, Liu YC, Semenza GL, Dang CV (2007) Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol 27:7381–7393

    Article  PubMed  CAS  Google Scholar 

  38. Rathinam R, Berrier A, Alahari SK (2012) Role of Rho GTPases and their regulators in cancer progression. Front Biosci 17:2561–2571

    Google Scholar 

  39. Struckhoff AP, Rana MK, Worthylake RA (2011) RhoA can lead the way in tumor cell invasion and metastasis. Front Biosci 16:1915–1926

    Article  PubMed  CAS  Google Scholar 

  40. Kikuchi K, Li X, Zheng Y, Takano Y (2011) Invasion of breast cancer cells into collagen matrix requires TGF-alpha and Cdc42 signaling. FEBS Lett 585:286–290

    Article  PubMed  CAS  Google Scholar 

  41. Chen B, Gao Y, Jiang T, Ding J, Zeng Y, Xu R, Jiang X (2011) Inhibition of tumor cell migration and invasion through knockdown of Rac1 expression in medulloblastoma cells. Cell Mol Neurobiol 31:251–257

    Article  PubMed  CAS  Google Scholar 

  42. Gao Y, Xie M, He ZP, Zhang X, Zheng JQ (2010) The effect of hypoxia on the expression of RHO/RHO signaling pathway and CTGF of human embryonic fibroblasts. Sichuan Da Xue Xue Bao Yi Xue Ban 41:946–950

    PubMed  CAS  Google Scholar 

  43. Lau CP, Huang L, Tsui SK, Ng PK, Leung PY, Kumta SM (2011) Pamidronate, farnesyl transferase, and geranylgeranyl transferase-I inhibitors affects cell proliferation, apoptosis, and OPG/RANKL mRNA expression in stromal cells of giant cell tumor of bone. J Orthop Res 29:403–413

    Article  PubMed  CAS  Google Scholar 

  44. van de Donk NW, Schotte D, Kamphuis MM, van Marion AM, van Kessel B, Bloem AC, Lokhorst HM (2003) Protein geranylgeranylation is critical for the regulation of survival and proliferation of lymphoma tumor cells. Clin Cancer Res 9:5735–5748

    PubMed  Google Scholar 

  45. Sane KM, Mynderse M, Lalonde DT, Dean IS, Wojtkowiak JW, Fouad F, Borch RF, Reiners JJ Jr, Gibbs RA, Mattingly RR (2010) A novel geranylgeranyl transferase inhibitor in combination with lovastatin inhibits proliferation and induces autophagy in STS-26T MPNST cells. J Pharmacol Exp Ther 333:23–33

    Article  PubMed  CAS  Google Scholar 

  46. Unlu S, Mason CD, Schachter M, Hughes AD (2000) Perillyl alcohol, an inhibitor of geranylgeranyl transferase, induces apoptosis of immortalized human vascular smooth muscle cells in vitro. J Cardiovasc Pharmacol 35:341–344

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The project was supported by National Natural Science Foundation of China (No. 81072072; No. 31070933); Natural Science Foundation of Jiangsu province (No. BK2011195); the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); and Program for New Century Excellent Talents in University (NCET-10-0181).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical College, 99 West Huai-hai Road, Xuzhou, 221002, Jiangsu, People’s Republic of China

    Xiuping Zhou, Qiong Shi & Rutong Yu

  2. Lab of Neurosurgery, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, 221002, Jiangsu, People’s Republic of China

    Xiuping Zhou, Qiong Shi & Rutong Yu

  3. Key Laboratory of Brain Disease Biology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, People’s Republic of China

    Xiuping Zhou, Qiong Shi & Rutong Yu

  4. The Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, People’s Republic of China

    Zhi Liu, Jiantong Jiao, Wenbin Bian, Xu Song, Jianbing Mo, Ben sang, Yinfu Xu, Jinming Qian & Yuewen Chao

Authors
  1. Xiuping Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiong Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiantong Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenbin Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xu Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jianbing Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ben sang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yinfu Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jinming Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuewen Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rutong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiuping Zhou or Rutong Yu.

Additional information

Xiuping Zhou, Zhi Liu and Qiong Shi contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, X., Liu, Z., Shi, Q. et al. Geranylgeranyltransferase I regulates HIF-1α promoting glioblastoma cell migration and invasion. J Neurooncol 112, 365–374 (2013). https://doi.org/10.1007/s11060-013-1081-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-013-1081-y

Keywords

Search

Navigation