Skip to main content

Advertisement

SpringerLink
Log in

Blocking the bFGF/STAT3 interaction through specific signaling pathways induces apoptosis in glioblastoma cells

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

Abstract

We have reported that basic fibroblast growth factor (bFGF) demonstrates an intimate connection with signal transducer and activator of transcription 3 (STAT3) in malignant brain tumor cells. However, its mechanisms are still unclear. In this study, we used inhibitors to block specific signaling pathways, including JAK, PI3K/Akt, and Src pathways, to explore how bFGF mediates crosstalk with STAT3 in two glioblastoma(GBM) cell lines: U251 (mutant p53) and U87 (wild-type p53). Furthermore, we explored how the bFGF/STAT3 pathway affects GBM cell apoptosis. Our results suggest that bFGF can induce the activation of STAT3 mainly through the JAK and PI3K/Akt pathways, and that siRNA-mediated knockdown of STAT3 markedly reduces the bFGF levels in U251 cells. Our results also suggest that STAT3 knockdown increases the expression of pro-apoptotic genes and decreases the expression of anti-apoptotic genes, subsequently collapsing the mitochondrial membrane potentials in vitro and impairs tumor growth in vivo.

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

Similar content being viewed by others

References

  1. Niu G, Wright KL, Huang M et al (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21(13):2000–2008

    Article  PubMed  CAS  Google Scholar 

  2. Feng X, Zhang B, Wang J et al (2011) Adenovirus-mediated transfer of siRNA against basic fibroblast growth factor mRNA enhances the sensitivity of glioblastoma cells to chemotherapy. Med Oncol 28(1):24–30

    Article  PubMed  Google Scholar 

  3. Ferla R, Haspinger E, Surmacz E (2012) Metformin inhibits leptin-induced growth and migration of glioblastoma cells. Oncol Lett 4(5):1077–1081

    PubMed  CAS  PubMed Central  Google Scholar 

  4. Sledzevskaia IK, Kravtsova LA, Golovkov I et al (1990) The results of the rehabilitative treatment of myocardial infarct patients activated at the hospital stage according to an accelerated program. Ter Arkh 62(8):28–30

    PubMed  CAS  Google Scholar 

  5. Liu Y, Li C, Lin J (2010) STAT3 as a therapeutic target for glioblastoma. Anticancer Agents Med Chem 10(7):512–519

    Article  PubMed  CAS  Google Scholar 

  6. Abou-Ghazal M, Yang DS, Qiao W et al (2008) The incidence, correlation with tumor-infiltrating inflammation, and prognosis of phosphorylated STAT3 expression in human gliomas. Clin Cancer Res 14(24):8228–8235

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Yang F, Brown C, Buettner R et al (2010) Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol Cancer Ther 9(4):953–962

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Johnson FM, Saigal B, Tran H et al (2007) Abrogation of signal transducer and activator of transcription 3 reactivation after Src kinase inhibition results in synergistic antitumor effects. Clin Cancer Res 13(14):4233–4244

    Article  PubMed  CAS  Google Scholar 

  9. Gately S, Soff GA, Brem S (1995) The potential role of basic fibroblast growth factor in the transformation of cultured primary human fetal astrocytes and the proliferation of human glioma (U-87) cells. Neurosurgery 37(4): 723–730; discussion 30–2

  10. Fukui S, Nawashiro H, Otani N et al (2003) Nuclear accumulation of basic fibroblast growth factor in human astrocytic tumors. Cancer 97(12):3061–3067

    Article  PubMed  CAS  Google Scholar 

  11. Feng XQ, Wang JH, Xu XN et al (2010) Anti-glioma effect of combination of bFGF-siRNA and Vpr in nude mice. Zhonghua Zhong Liu Za Zhi 32(10):725–728

    PubMed  CAS  Google Scholar 

  12. Liu J, Xu X, Feng X et al (2011) Adenovirus-mediated delivery of bFGF small interfering RNA reduces STAT3 phosphorylation and induces the depolarization of mitochondria and apoptosis in glioma cells U251. J Exp Clin Cancer Res 30:80

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ple PA, Green TP, Hennequin LF et al (2004) Discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of c-Src. J Med Chem 47(4):871–887

    Article  PubMed  CAS  Google Scholar 

  14. Li P, Nijhawan D, Budihardjo I et al (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91(4):479–489

    Article  PubMed  CAS  Google Scholar 

  15. Yu H, Jove R (2004) The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 4(2):97–105

    Article  PubMed  CAS  Google Scholar 

  16. Michaud-Levesque J, Bousquet-Gagnon N, Beliveau R (2012) Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration. Exp Cell Res 318(8):925–935

    Article  PubMed  CAS  Google Scholar 

  17. Jiang R, Tan Z, Deng L et al (2011) Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 54(3):900–909

    Article  PubMed  CAS  Google Scholar 

  18. Li HS, Yang CY, Nallaparaju KC et al (2012) The signal transducers STAT5 and STAT3 control expression of Id2 and E2-2 during dendritic cell development. Blood 120(22):4363–4373

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Lu Y, Yue X, Cui Y et al (2013) MicroRNA-124 suppresses growth of human hepatocellular carcinoma by targeting STAT3. Biochem Biophys Res Commun 441(4):873–879

    Article  PubMed  CAS  Google Scholar 

  20. Li Y, Xia JY, Chen W et al (2013) Effects of Ling Qi Juan Gan capsule drug-containing serum on PDGF-induced proliferation and JAK/STAT signaling of HSC-T6 cells. Zhonghua Gan Zang Bing Za Zhi 21(9):663–667

    PubMed  Google Scholar 

  21. Fasler-Kan E, Barteneva NS, Ketterer S et al (2013) Human cytokines activate JAK-STAT signaling pathway in porcine ocular tissue. Xenotransplantation 20(6):469–480

    Article  PubMed  Google Scholar 

  22. Brantley EC, Nabors LB, Gillespie GY et al (2008) Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression. Clin Cancer Res 14(15):4694–4704

    Article  PubMed  CAS  Google Scholar 

  23. Lo HW, Cao X, Zhu H et al (2008) Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Cancer Res 14(19):6042–6054

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Udayakumar TS, Stratton MS, Nagle RB et al (2002) Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3. Neoplasia 4(1):60–67

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Kozawa O, Otsuka T, Uematsu T (2002) Leukemia inhibitory factor enhances bFGF-induced IL-6 synthesis in osteoblasts: involvement of JAK2/STAT3. Cell Signal 14(4):311–315

    Article  PubMed  CAS  Google Scholar 

  26. Epling-Burnette PK, Liu JH, Catlett-Falcone R et al (2001) Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 107(3):351–362

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Qian C, Wang J, Yao J et al (2013) Involvement of nuclear JAK2 signaling in AG490-induced apoptosis of gastric cancer cells. Anat Rec (Hoboken) 296(12):1865–1873

    Article  CAS  Google Scholar 

  28. Duan W, Yang Y, Yi W et al (2013) New role of JAK2/STAT3 signaling in endothelial cell oxidative stress injury and protective effect of melatonin. PLoS ONE 8(3):e57941

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Puls LN, Eadens M, Messersmith W (2011) Current status of SRC inhibitors in solid tumor malignancies. Oncologist 16(5):566–578

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. de Wispelaere M, LaCroix AJ, Yang PL (2013) The small molecules AZD0530 and dasatinib inhibit dengue virus RNA replication via Fyn kinase. J Virol 87(13):7367–7381

    Article  PubMed  PubMed Central  Google Scholar 

  31. Musumeci F, Schenone S, Brullo C et al (2012) An update on dual Src/Abl inhibitors. Future Med Chem 4(6):799–822

    Article  PubMed  CAS  Google Scholar 

  32. Ruan GX, Kazlauskas A (2012) Axl is essential for VEGF-A-dependent activation of PI3K/Akt. EMBO J 31(7):1692–1703

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Tong B, Lu D, Wei Z et al (2012) Gleditsioside B, a triterpene saponin isolated from the anomalous fruits of Gleditsia sinensis Lam., abrogates bFGF-induced endothelial cell migration through preventing the activation of MMP-2 and FAK via inhibiting ERK and PI3K/AKT signaling pathways. Vascul Pharmacol 58(1–2):118–129

    PubMed  Google Scholar 

  34. Workman P, Clarke PA, Raynaud FI et al (2010) Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res 70(6):2146–2157

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Workman P, Clarke PA, Guillard S et al (2006) Drugging the PI3 kinome. Nat Biotechnol 24(7):794–796

    Article  PubMed  CAS  Google Scholar 

  36. Tchirkov A, Khalil T, Chautard E et al (2007) Interleukin-6 gene amplification and shortened survival in glioblastoma patients. Br J Cancer 96(3):474–476

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Weissenberger J, Loeffler S, Kappeler A et al (2004) IL-6 is required for glioma development in a mouse model. Oncogene 23(19):3308–3316

    Article  PubMed  CAS  Google Scholar 

  38. Salmaggi A, Eoli M, Frigerio S et al (2003) Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. J Neurooncol 62(3):297–303

    Article  PubMed  Google Scholar 

  39. Liu Q, Li G, Li R et al (2010) IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines. J Neurooncol 100(2):165–176

    Article  PubMed  CAS  Google Scholar 

  40. Son MJ, Kim JS, Kim MH et al (2006) Combination treatment with temozolomide and thalidomide inhibits tumor growth and angiogenesis in an orthotopic glioma model. Int J Oncol 28(1):53–59

    PubMed  CAS  Google Scholar 

  41. Cregan SP, Dawson VL, Slack RS (2004) Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 23(16):2785–2796

    Article  PubMed  CAS  Google Scholar 

  42. Bourke LT, Knight RA, Latchman DS et al (2013) Signal transducer and activator of transcription-1 localizes to the mitochondria and modulates mitophagy. JAKSTAT 2(4):e25666

    PubMed  PubMed Central  Google Scholar 

  43. Sugioka R, Shimizu S, Funatsu T et al (2003) BH4-domain peptide from Bcl-xL exerts anti-apoptotic activity in vivo. Oncogene 22(52):8432–8440

    Article  PubMed  CAS  Google Scholar 

  44. Chan SL, Yu VC (2004) Proteins of the bcl-2 family in apoptosis signalling: from mechanistic insights to therapeutic opportunities. Clin Exp Pharmacol Physiol 31(3):119–128

    Article  PubMed  CAS  Google Scholar 

  45. Gielen PR, Aftab Q, Ma N et al (2013) Connexin43 confers temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmacology 75:539–548

    Article  PubMed  CAS  Google Scholar 

  46. Sumalatha KR, Abiramasundari G, Chetan GK et al (2014) XIAP inhibitor and antiestrogen embelin abrogates metastasis and augments apoptosis in estrogen receptor positive human breast adenocarcinoma cell line MCF-7. Mol Biol Rep 41(2):935–946

    Article  PubMed  CAS  Google Scholar 

  47. Yang J, Ouyang J, Ouyang L et al (2013) Inhibition of cell proliferation and increase of chemosensitivity by simultaneous knockdown of XIAP and survivin in pancreatic carcinoma cells. Oncol Res 21(1):43–50

    Article  PubMed  Google Scholar 

  48. Xin H, Liu XH, Zhu YZ (2009) Herba leonurine attenuates doxorubicin-induced apoptosis in H9c2 cardiac muscle cells. Eur J Pharmacol 612(1–3):75–79

    Article  PubMed  CAS  Google Scholar 

  49. Nykky NJ, Vuento M, Gilbert L (2014) Role of mitochondria in parvovirus pathology. PLoS One 9(1):e86124

    Article  PubMed  PubMed Central  Google Scholar 

  50. Matsumoto Y, Cao E, Ueoka R (2013) Growth inhibition by novel liposomes including trehalose surfactant against hepatocarcinoma cells along with apoptosis. Anticancer Res 33(11):4727–4740

    PubMed  CAS  Google Scholar 

  51. Gordon N, Kleinerman ES (2010) Aerosol therapy for the treatment of osteosarcoma lung metastases: targeting the Fas/FasL pathway and rationale for the use of gemcitabine. J Aerosol Med Pulm Drug Deliv 23(4):189–196

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (81101911), National Clinical Key Specialty Project Foundation of the Ministry of Health, P. R. China (2011873), the Tianjin Science and Technology Committee (11JCYBJC12100, 12ZCDZSY17700, 14JCZDJC35600), the Foundation of Tianjin Bureau of Public Health (11KG115, 2011KR11, 2012KR07) and the China Scholarship Council.

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, 300060, People’s Republic of China

    Jingchao Wu, Jialin Li, Jun Liu, Xiuyu Wang, Jinhuan Wang & Xiaoguang Tong

  2. Department of Neurosurgery, Tianjin First Center Hospital, Tianjin, 300192, People’s Republic of China

    Xuequan Feng

  3. Clinical Laboratory, Tianjin Huanhu Hospital, Tianjin, 300060, People’s Republic of China

    Biao Zhang

  4. Key Laboratory for Critical Care Medicine of the Ministry of Health, Tianjin First Center Hospital, Tianjin, 300192, People’s Republic of China

    Xinnv Xu

Authors
  1. Jingchao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuequan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Biao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jialin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xinnv Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiuyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jinhuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaoguang Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jinhuan Wang or Xiaoguang Tong.

Additional information

Jingchao Wu and Xuequan Feng contributed equally to this work and should be considered as co-first author.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, J., Feng, X., Zhang, B. et al. Blocking the bFGF/STAT3 interaction through specific signaling pathways induces apoptosis in glioblastoma cells. J Neurooncol 120, 33–41 (2014). https://doi.org/10.1007/s11060-014-1529-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1529-8

Keywords

Search

Navigation