Skip to main content

Advertisement

SpringerLink
Log in

Calpain suppresses cell growth and invasion of glioblastoma multiforme by producing the cleavage of filamin A

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Filamin A is the most widely expressed isoform of filamin in mammalian tissues. It can be hydrolyzed by Calpain, producing a 90-kDa carboxyl-terminal fragment (ABP90). Calpeptin is a chemical inhibitor of Calpain, which can inhibit this effect. It has been shown that ABP90 acts as a transcription factor which is involved in mediating cell signaling. However, the significance of ABP90 and its clinical signature with underlying mechanisms have not been well studied in glioblastoma multiforme (GBM).

Methods

ABP90 protein was measured in 36 glioma patients by Western blot. Human GBM cell lines U87 and A172 were used to clarify the precise role of ABP90. CCK-8 assay was used to analyze the cell viability. Transwell invasion assay and wound healing assay were used to analyze the migration and invasion. Expression of matrix metalloproteinase 2/tissue inhibitors of metalloproteinase 2 (MMP2/TIMP2) protein was analyzed by Western blot.

Results

ABP90 protein expression was lower in GBM tissues. The patients with low ABP90 protein expression had a shorter OS time (p = 0.046). After being treated with Calpain, the expression of ABP90 was upregulated, which led to a decline of cell viability, enhanced the efficacy of temozolomide and restrained the cell invasion. Calpeptin could inhibit the effect. The mechanism might be involved in the balance of MMP2/TIMP2.

Conclusions

Our present data suggest that ABP90 expression is a significant prognostic factor and may play an important role in cell viability, chemotherapeutic sensitivity and invasion of GBM.

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
Fig. 6

Similar content being viewed by others

References

  1. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  CAS  PubMed  Google Scholar 

  2. Verhaak RG, Hoadley KA, Purdom E et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466

    Article  CAS  PubMed  Google Scholar 

  4. Van Meir EG, Hadjipanayis CG, Norden AD et al (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60(3):166–193

    Article  PubMed  PubMed Central  Google Scholar 

  5. Purow B, Schiff D (2009) Advances in the genetics of glioblastoma: are we reaching critical mass? Nat Rev Neurol 5(8):419–426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nakamura F, Stossel TP, Hartwig JH (2011) The filamins: organizers of cell structure and function. Cell Adhes Migr 5(2):160–169

    Article  Google Scholar 

  7. Berrou E, Adam F, Lebret M et al (2017) Gain-of-function mutation in filamin A potentiates platelet integrin alphaIIbbeta3 activation. Arterioscler Thromb Vasc Biol 37(6):1087–1097

    Article  CAS  PubMed  Google Scholar 

  8. Gorlin JB, Yamin R, Egan S et al (1990) Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring. J Cell Biol 111(3):1089–1105

    Article  CAS  PubMed  Google Scholar 

  9. van der Flier A, Sonnenberg A (2001) Structural and functional aspects of filamins. Biochem Biophys Acta 1538(2–3):99–117

    Article  PubMed  Google Scholar 

  10. Deng W, Lopez-Camacho C, Tang JY et al (2012) Cytoskeletal protein filamin A is a nucleolar protein that suppresses ribosomal RNA gene transcription. Proc Natl Acad Sci USA 109(5):1524–1529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mooso BA, Vinall RL, Tepper CG et al (2012) Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization. Endocr Relat Cancer 19(6):759–777

    Article  CAS  PubMed  Google Scholar 

  12. Planaguma J, Minsaas L, Pons M et al (2012) Filamin A-hinge region 1-EGFP: a novel tool for tracking the cellular functions of filamin A in real-time. PLoS ONE 7(8):e40864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu T, Mendes DE, Berkman CE (2014) Prolonged androgen deprivation leads to overexpression of calpain 2: implications for prostate cancer progression. Int J Oncol 44(2):467–472

    Article  CAS  PubMed  Google Scholar 

  14. Hastings MH, Gong K, Freibauer A et al (2017) Novel calpain families and novel mechanisms for calpain regulation in Aplysia. PLoS ONE 12(10):e0186646

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Savoy RM, Ghosh PM (2013) The dual role of filamin A in cancer: can't live with (too much of) it, can't live without it. Endocr Relat Cancer 20(6):R341–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chantaravisoot N, Wongkongkathep P, Loo JA et al (2015) Significance of filamin A in mTORC2 function in glioblastoma. Mol Cancer 14:127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Robertson SP, Twigg SR, Sutherland-Smith AJ et al (2003) Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33(4):487–491

    Article  CAS  PubMed  Google Scholar 

  18. Saido TC, Sorimachi H, Suzuki K (1994) Calpain: new perspectives in molecular diversity and physiological-pathological involvement. FASEB J 8(11):814–822

    Article  CAS  PubMed  Google Scholar 

  19. Ray SK, Wilford GG, Crosby CV et al (1999) Diverse stimuli induce calpain overexpression and apoptosis in C6 glioma cells. Brain Res 829(1–2):18–27

    Article  CAS  PubMed  Google Scholar 

  20. Ray SK, Fidan M, Nowak MW et al (2000) Oxidative stress and Ca2+ influx upregulate calpain and induce apoptosis in PC12 cells. Brain Res 852(2):326–334

    Article  CAS  PubMed  Google Scholar 

  21. Yang Z, Lin F, Robertson CS et al (2014) Dual vulnerability of TDP-43 to calpain and caspase-3 proteolysis after neurotoxic conditions and traumatic brain injury. J Cereb Blood Flow Metab 34(9):1444–1452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Catzavelos C, Bhattacharya N, Ung YC et al (1997) Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med 3(2):227–230

    Article  CAS  PubMed  Google Scholar 

  23. Chappuis PO, Donato E, Goffin JR et al (2005) Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment. Ann Oncol 16(5):735–742

    Article  CAS  PubMed  Google Scholar 

  24. Shao QQ, Zhang TP, Zhao WJ et al (2016) Filamin A: insights into its exact role in cancers. Pathol Oncol Res POR 22(2):245–252

    Article  PubMed  CAS  Google Scholar 

  25. Fucini P, Koppel B, Schleicher M et al (1999) Molecular architecture of the rod domain of the Dictyostelium gelation factor (ABP120). J Mol Biol 291(5):1017–1023

    Article  CAS  PubMed  Google Scholar 

  26. Krebs K, Ruusmann A, Simonlatser G et al (2015) Expression of FLNa in human melanoma cells regulates the function of integrin alpha1beta1 and phosphorylation and localisation of PKB/AKT/ERK1/2 kinases. Eur J Cell Biol 94(12):564–575

    Article  CAS  PubMed  Google Scholar 

  27. Sun GG, Lu YF, Zhang J et al (2014) Filamin A regulates MMP-9 expression and suppresses prostate cancer cell migration and invasion. Tumour Biol 35(4):3819–3826

    Article  CAS  PubMed  Google Scholar 

  28. Xu Y, Bismar TA, Su J et al (2010) Filamin A regulates focal adhesion disassembly and suppresses breast cancer cell migration and invasion. J Exp Med 207(11):2421–2437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang K, Zhu T, Gao D et al (2014) Filamin A expression correlates with proliferation and invasive properties of human metastatic melanoma tumors: implications for survival in patients. J Cancer Res Clin Oncol 140(11):1913–1926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wieczorek K, Wiktorska M, Sacewicz-Hofman I et al (2017) Filamin A upregulation correlates with Snail-induced epithelial to mesenchymal transition (EMT) and cell adhesion but its inhibition increases the migration of colon adenocarcinoma HT29 cells. Exp Cell Res 359(1):163–170

    Article  CAS  PubMed  Google Scholar 

  31. Wensheng D (2012) Cytoskeletal protein filamin A is a nucleolar protein that suppresses ribosomal RNA gene transcription. Proc Natl Acad Sci USA 5(109):1524–1529

    Google Scholar 

  32. Storr SJ, Carragher NO, Frame MC et al (2011) The calpain system and cancer. Nat Rev Cancer 11(5):364–374

    Article  CAS  PubMed  Google Scholar 

  33. Wu HY, Lynch DR (2006) Calpain and synaptic function. Mol Neurobiol 33(3):215–236

    Article  PubMed  Google Scholar 

  34. Chen J, Wu Y, Zhang L et al (2019) Evidence for calpains in cancer metastasis. J Cell Physiol 234(6):8233–8240

    Article  CAS  PubMed  Google Scholar 

  35. Liu J, Liu MC, Wang KK (2008) Calpain in the CNS: from synaptic function to neurotoxicity. Sci Signal 1(14):re1

    Article  PubMed  Google Scholar 

  36. Su Y, Cui Z, Li Z et al (2006) Calpain-2 regulation of VEGF-mediated angiogenesis. FASEB J 20(9):1443–1451

    Article  CAS  PubMed  Google Scholar 

  37. Bramhall SR, Neoptolemos JP, Stamp GW et al (1997) Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol 182(3):347–355

    Article  CAS  PubMed  Google Scholar 

  38. Fillmore HL, VanMeter TE, Broaddus WC (2001) Membrane-type matrix metalloproteinases (MT-MMPs): expression and function during glioma invasion. J Neurooncol 53(2):187–202

    Article  CAS  PubMed  Google Scholar 

  39. Pornchai OC, Rhys-Evans PH, Eccles SA (2001) Expression of matrix metalloproteinases and their inhibitors correlates with invasion and metastasis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 127(7):813–820

    Google Scholar 

  40. Theret N, Musso O, Turlin B et al (2001) Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas. Hepatology 34(1):82–88

    Article  CAS  PubMed  Google Scholar 

  41. Kallakury BV, Karikehalli S, Haholu A et al (2001) Increased expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinases 1 and 2 correlate with poor prognostic variables in renal cell carcinoma. Clin Cancer Res 7(10):3113–3119

    CAS  PubMed  Google Scholar 

  42. Tanaka K, Iwamoto Y, Ito Y et al (1995) Cyclic AMP-regulated synthesis of the tissue inhibitors of metalloproteinases suppresses the invasive potential of the human fibrosarcoma cell line HT1080. Cancer Res 55(13):2927–2935

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Xianbin Chen (Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University) for providing special support and experimental assistance during this study.

Funding

This work was supported by grants from the Natural Science Foundation of Zhejiang Province (LY16H160051, LQ17C060002, LY17H160052, LY19C070002), Wenzhou Municipal Science and Technology Bureau (Y20170088, Y20170085).

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

      Lin Cai, Qun Li, Chengde Wang, Ming Tu, Zhangzhang Zhu, Zhipeng Su & Xianghe Lu

    2. Department of Radiation Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

      Wenfeng Li

    Authors
    1. Lin Cai
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Qun Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Wenfeng Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Chengde Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ming Tu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Zhangzhang Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Zhipeng Su
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Xianghe Lu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Zhipeng Su or Xianghe Lu.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no competing interests.

    Additional information

    Publisher's Note

    Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

    Lin Cai and Qun Li contributed equally to this work and are co-first authors.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary file1 (DOCX 125 kb)

    Supplementary file2 (DOCX 183 kb)

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Cai, L., Li, Q., Li, W. et al. Calpain suppresses cell growth and invasion of glioblastoma multiforme by producing the cleavage of filamin A. Int J Clin Oncol 25, 1055–1066 (2020). https://doi.org/10.1007/s10147-020-01636-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10147-020-01636-7

    Keywords

    Search

    Navigation