Skip to main content

Advertisement

SpringerLink
Log in

TRPM7 channel inhibition mediates midazolam-induced proliferation loss in human malignant glioma

  • Original Article
  • Published:
Tumor Biology

Abstract

The melastatin-like transient receptor potential 7 (TRPM7) has been implicated in proliferation or apoptosis of some cancers, indicating the potential of TRPM7 as an anti-anaplastic target. Here, we identified the characteristic TRPM7 channel currents in human malignant glioma MGR2 cells, which could be blocked by a pharmacologic inhibitor Gd3+. We mined the clinical sample data from Oncomine Database and found that human malignant glioma tissues expressed higher TRPM7 mRNA than normal brain ones. Importantly, we identified a widely used clinical anesthetic midazolam as a TRPM7 inhibitor. Midazolam treatment for seconds suppressed the TRPM7 currents and calcium influx, and treatment for 48 h inhibited the TRPM7 expression. The inhibitory effect on TRPM7 accounts for the proliferation loss and G0/G1 phase cell cycle arrest induced by midazolam. Our data demonstrates that midazolam represses proliferation of human malignant glioma cells through inhibiting TRPM7 currents, which may be further potentiated by suppressing the expression of TRPM7. Our result indicates midazolam as a pharmacologic lead compound with brain-blood barrier permeability for targeting TRPM7 in the glioma.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yee NS, Kazi AA, Yee RK. Cellular and developmental biology of TRPM7 channel-kinase: implicated roles in cancer. Cells. 2014;3:751–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Guilbert A, Gautier M, Dhennin-Duthille I, Haren N, Sevestre H, Ouadid-Ahidouch H. Evidence that TRPM7 is required for breast cancer cell proliferation. Am J Physiol Cell Physiol. 2009;297:C493–502.

    Article  CAS  PubMed  Google Scholar 

  3. Sun YY, Sukumaran P, Varma A, Derry S, Sahmoun AE, Singh BB. Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells. Bba-Mol. Cell Res. 2014;1843:1839–50.

    CAS  Google Scholar 

  4. Rybarczyk P, Gautier M, Hague F, Dhennin-Duthille I, Chatelain D, Kerr-Conte J, Pattou F, Regimbeau JM, Sevestre H, Ouadid-Ahidouch H. Transient receptor potential melastatin-related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas and regulates human pancreatic cancer cell migration. Int J Cancer J Int du Cancer. 2012;131:E851–61.

    Article  CAS  Google Scholar 

  5. Wang J, Liao QJ, Zhang Y, Zhou H, Luo CH, Tang J, Wang Y, Tang Y, Zhao M, Zhao XH, Zhang QY, Xiao L. TRPM7 is required for ovarian cancer cell growth, migration and invasion. Biochem Biophys Res Commun. 2014;454:547–53.

    Article  CAS  PubMed  Google Scholar 

  6. Jiang J, Li MH, Inoue K, Chu XP, Seeds J, Xiong ZG. Transient receptor potential melastatin 7-like current in human head and neck carcinoma cells: role in cell proliferation. Cancer Res. 2007;67:10929–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko C, Barnholtz-Sloan J. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-Oncology. 2014;16(Suppl 4):iv1–63.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

    Article  CAS  PubMed  Google Scholar 

  9. Lanzetta G, Minniti G. Treatment of glioblastoma in elderly patients: an overview of current treatments and future perspective. Tumori. 2010;96:650–8.

    PubMed  Google Scholar 

  10. Chamberlain MC. Temozolomide: therapeutic limitations in the treatment of adult high-grade gliomas. Expert Rev Neurother. 2010;10:1537–44.

    Article  CAS  PubMed  Google Scholar 

  11. Mandrioli R, Mercolini L, Raggi MA. Benzodiazepine metabolism: an analytical perspective. Curr Drug Metab. 2008;9:827–44.

    Article  CAS  PubMed  Google Scholar 

  12. Ali-Osman F, Stein DE, Renwick A. Glutathione content and glutathione-s-transferase expression in 1,3-bis(2-chloroethyl)-1-nitrosourea-resistant human malignant astrocytoma cell lines. Cancer Res. 1990;50:6976–80.

    CAS  PubMed  Google Scholar 

  13. Callera GE, He Y, Yogi A, Montezano AC, Paravicini T, Yao G, Touyz RM. Regulation of the novel Mg2+ transporter transient receptor potential melastatin 7 (TRPM7) cation channel by bradykinin in vascular smooth muscle cells. J Hypertens. 2009;27:155–66.

    Article  CAS  PubMed  Google Scholar 

  14. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. Oncomine: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6:1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, Varambally S, Ghosh D, Chinnaiyan AM. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007;9:166–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF, de Tribolet N, Regli L, Wick W, Kouwenhoven MC, Hainfellner JA, Heppner FL, Dietrich PY, Zimmer Y, Cairncross JG, Janzer RC, Domany E, Delorenzi M, Stupp R, Hegi ME. Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:3015–24.

    Article  CAS  Google Scholar 

  17. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9:391–403.

    Article  CAS  PubMed  Google Scholar 

  18. Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S, Passaniti A, Menon J, Walling J, Bailey R, Rosenblum M, Mikkelsen T, Fine HA. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell. 2006;9:287–300.

    Article  CAS  PubMed  Google Scholar 

  19. Bredel M, Bredel C, Juric D, Harsh GR, Vogel H, Recht LD, Sikic BI. Functional network analysis reveals extended gliomagenesis pathway maps and three novel MYC-interacting genes in human gliomas. Cancer Res. 2005;65:8679–89.

    Article  CAS  PubMed  Google Scholar 

  20. Dou Y, Li Y, Chen J, Wu S, Xiao X, Xie S, Tang L, Yan M, Wang Y, Lin J, Zhu W, Yan G. Inhibition of cancer cell proliferation by midazolam by targeting transient receptor potential melastatin 7. Oncol Lett. 2013;5:1010–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zholos A, Beck B, Sydorenko V, Lemonnier L, Bordat P, Prevarskaya N, Skryma R. Ca(2+)- and volume-sensitive chloride currents are differentially regulated by agonists and store-operated Ca2+ entry. J Gen Physiol. 2005;125:197–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Clark K, Langeslag M, van Leeuwen B, Ran L, Ryazanov AG, Figdor CG, Moolenaar WH, Jalink K, van Leeuwen FN. TRPM7, a novel regulator of actomyosin contractility and cell adhesion. EMBO J. 2006;25:290–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Roderick HL, Cook SJ. Ca2+ signalling checkpoints in cancer: Remodelling Ca2+ for cancer cell proliferation and survival. Nature reviews. Cancer. 2008;8:361–75.

    CAS  PubMed  Google Scholar 

  24. Mishra SK, Kang JH, Lee CW, Oh SH, Ryu JS, Bae YS, Kim HM. Midazolam induces cellular apoptosis in human cancer cells and inhibits tumor growth in xenograft mice. Mol Cells. 2013;36:219–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yogi A, Callera GE, Tostes R, Touyz RM. Bradykinin regulates calpain and proinflammatory signaling through TRPM7-sensitive pathways in vascular smooth muscle cells. Am J Physiol Regul, Integr Comp Physiol. 2009;296:R201–7.

    Article  CAS  Google Scholar 

  26. Langeslag M, Clark K, Moolenaar WH, van Leeuwen FN, Jalink K. Activation of TRPM7 channels by phospholipase C-coupled receptor agonists. J Biol Chem. 2007;282:232–9.

    Article  CAS  PubMed  Google Scholar 

  27. Sun Y, Selvaraj S, Varma A, Derry S, Sahmoun AE, Singh BB. Increase in serum Ca2+/Mg2+ ratio promotes proliferation of prostate cancer cells by activating TRPM7 channels. J Biol Chem. 2013;288:255–63.

    Article  CAS  PubMed  Google Scholar 

  28. Dziegielewska B, Gray LS, Dziegielewski J. T-type calcium channels blockers as new tools in cancer therapies. Pflugers Arch: Eur J Physiol. 2014;466:801–10.

    Article  CAS  Google Scholar 

  29. Kim BJ, Park EJ, Lee JH, Jeon JH, Kim SJ, So I. Suppression of transient receptor potential melastatin 7 channel induces cell death in gastric cancer. Cancer Sci. 2008;99:2502–9.

    Article  CAS  PubMed  Google Scholar 

  30. Gao H, Chen X, Du X, Guan B, Liu Y, Zhang H. EGF enhances the migration of cancer cells by up-regulation of TRPM7. Cell Calcium. 2011;50:559–68.

    Article  CAS  PubMed  Google Scholar 

  31. Leng TD, Li MH, Shen JF, Liu ML, Li XB, Sun HW, Branigan D, Zeng Z, Si HF, Li J. Suppression of TRPM7 inhibits proliferation, migration, and invasion of malignant human glioma cells. CNS Neurosci Ther. 2015;21:252–61.

    Article  CAS  PubMed  Google Scholar 

  32. Liu M, Inoue K, Leng T, Guo S, Xiong ZG. Trpm7 channels regulate glioma stem cell through stat3 and notch signaling pathways. Cell Signal. 2014;26:2773–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Alptekin M, Eroglu S, Tutar E, Sencan S, Geyik M, Ulasli M, Demiryurek A, Camci C. Gene expressions of TRP channels in glioblastoma multiforme and relation with survival. Tumor Biol. 2015:1–5.

  34. Dhennin-Duthille I, Gautier M, Faouzi M, Guilbert A, Brevet M, Vaudry D, Ahidouch A, Sevestre H, Ouadid-Ahidouch H. High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol. 2011;28:813–22.

    Article  CAS  Google Scholar 

  35. Chen WL, Barszczyk A, Turlova E, Deurloo M, Liu B, Yang BB, Rutka JT, Feng ZP, Sun HS. Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation, migration and invasion. Oncotarget. 2015;6:16321–40.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Leng TD, Li MH, Shen JF, Liu ML, Li XB, Sun HW, Branigan D, Zeng Z, Si HF, Li J. Suppression of TRPM7 inhibits proliferation, migration, and invasion of malignant human glioma cells. Cns Neurosci Ther. 2014;21:252–61.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hanano T, Hara Y, Shi J, Morita H, Umebayashi C, Mori E, Sumimoto H, Ito Y, Mori Y, Inoue R. Involvement of TRPM7 in cell growth as a spontaneously activated Ca2+ entry pathway in human retinoblastoma cells. J Pharmacol Sci. 2004;95:403–19.

    Article  CAS  PubMed  Google Scholar 

  38. Chokshi R, Fruasaha P, Kozak JA. 2-aminoethyl diphenyl borinate (2-APB) inhibits TRPM7 channels through an intracellular acidification mechanism. Channels. 2012;6:362–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xie J, Li Y, Huang Y, Qiu P, Shu M, Zhu W, Ou Y, Yan G. Anesthetic pentobarbital inhibits proliferation and migration of malignant glioma cells. Cancer Lett. 2009;282:35–42.

    Article  CAS  PubMed  Google Scholar 

  40. Nordenberg J, Fenig E, Landau M, Weizman R, Weizman A. Effects of psychotropic drugs on cell proliferation and differentiation. Biochem Pharmacol. 1999;58:1229–36.

    Article  CAS  PubMed  Google Scholar 

  41. Chen J, Ouyang Y, Cao L, Zhu W, Zhou Y, Zhou Y, Zhang H, Yang X, Mao L, Lin S, Lin J, Hu J, Yan G. Diazepam inhibits proliferation of human glioblastoma cells through triggering a G0/G1 cell cycle arrest. J Neurosurg Anesthesiol. 2013;25:285–91.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Fundamental Research Funds for the Central Universities, China (13ykpy07), Science and Technology Planning Project of Guangdong Province, China (2014A020212149), Medical Scientific Research Foundation of Guangdong Province, China (A2015102), Guangdong Natural Science Foundation (S2013010016308), and China Postdoctoral Science Foundation (2013M542162).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China

    Jingkao Chen, Fan Xing, Jialuo Mai, Jiayu Gu, Bingzheng Lu, Guangmei Yan & Wenbo Zhu

  2. School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, People’s Republic of China

    Jingkao Chen

  3. Department of Anesthesiology, Department of Pathology and Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China

    Yunling Dou, Xiaoke Zheng, Xiaofang Lu & Huawei Sun

  4. Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, 30329, USA

    Tiandong Leng

  5. Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China

    Ying Ouyang

  6. South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China

    Guangmei Yan & Wenbo Zhu

  7. Department of Anesthesiology, Stony Brook University Health Science Center, Stony Brook, NY, 11794-8480, USA

    Jun Lin

Authors
  1. Jingkao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yunling Dou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoke Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tiandong Leng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaofang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huawei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fan Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jialuo Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiayu Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bingzheng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Guangmei Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jun Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wenbo Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jun Lin or Wenbo Zhu.

Ethics declarations

Conflicts of interest

None

Additional information

Jingkao Chen and Yunling Dou contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, J., Dou, Y., Zheng, X. et al. TRPM7 channel inhibition mediates midazolam-induced proliferation loss in human malignant glioma. Tumor Biol. 37, 14721–14731 (2016). https://doi.org/10.1007/s13277-016-5317-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5317-2

Keywords

Search

Navigation