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Rabeprazole has efficacy per se and reduces resistance to temozolomide in glioma via EMT inhibition

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Abstract

Purpose

Epithelial to mesenchymal transition (EMT) is pivotal in embryonic development and wound healing, whereas in cancer it inflicts malignancy and drug resistance. The recognition of an EMT-like process in glioma is relatively new and its clinical and therapeutic significance has, as yet, not been fully elucidated. Here, we aimed to delineate the clinical significance of the EMT-like process in glioma and its therapeutic relevance to rabeprazole.

Methods

We investigated the expression profiles of EMT-associated proteins in primary glioma biopsies through Western blotting and immunohistochemistry, and correlated them with various clinicopathological features and data listed in the cancer genome atlas (TCGA). In addition, the anticancer efficacy of rabeprazole and its therapeutic relevance to EMT along with temozolomide chemo-sensitization were assessed using multiple cell-based assays, Western blotting and confocal imaging. For in vivo assessment, we used a stereotaxic C6-rat glioma model.

Results

Expression analysis of EMT-associated proteins in glioma biopsies, in conjunction with clinicopathological and TCGA dataset analyses, revealed non-canonical expression of E/N-cadherin and upregulation of GFAP, vimentin and β-catenin. The increased expression of EMT-associated proteins may attribute to glioma malignancy and a poor patient prognosis. Subsequent in vitro studies revealed that rabeprazole treatment attenuated glioma cell growth and migration, and induced apoptosis. Rabeprazole suppressed EMT by impeding AKT/GSK3β phosphorylation and/or NF-κB signaling and sensitized temozolomide resistance. Additional in vivo studies showed restricted tumor growth and inhibited expression of EMT-associated proteins after rabeprazole treatment.

Conclusions

Our data revealed (i) a clinical association of the EMT-like process with glioma malignancy and a poor survival and (ii) an anticancer and temozolomide sensitizing effect of rabeprazole by repressing EMT.

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Data availability 

All data are available in the paper and/or its supplementary files.

Abbreviations

GBM:

Glioblastoma multiforme

EMT:

epithelial to mesenchymal transition

PPI:

Proton pump inhibitor

NF-κB:

Nuclear factor kappa light chain enhancer of activated B cells

AKT:

Protein kinase B

GSK3β:

Glycogen synthase kinase-3β

TMZ:

Temozolomide

References

  1. Q.T. Ostrom, H. Gittleman, J. Xu, C. Kromer, Y. Wolinsky, C. Kruchko, J.S. Barnholtz-Sloan, CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013. Neuro-Oncology 18 (suppl_5), v1-v75 (2016).  https://doi.org/10.1093/neuonc/now207

  2. D. Beier, J.B. Schulz, C.P. Beier, Chemoresistance of glioblastoma cancer stem cells–much more complex than expected. Mol. Cancer. 10, 128 (2011). https://doi.org/10.1186/1476-4598-10-128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. F.B. Furnari, T. Fenton, R.M. Bachoo, A. Mukasa, J.M. Stommel, A. Stegh, W.C. Hahn, K.L. Ligon, D.N. Louis, C. Brennan, L. Chin, R.A. DePinho, W.K. Cavenee, Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes. Dev. 21, 2683–2710 (2007). https://doi.org/10.1101/gad.1596707

  4. Y.P. Ramirez, J.L. Weatherbee, R.T. Wheelhouse, A.H. Ross, Glioblastoma multiforme therapy and mechanisms of resistance. Pharmaceuticals. (Basel). 6(12), 1475–1506 (2013). https://doi.org/10.3390/ph6121475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. F. Marcucci, G. Stassi, R. De Maria, Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat. Rev. Drug Discov. 15(5), 311–325 (2016). https://doi.org/10.1038/nrd.2015.13

    Article  CAS  PubMed  Google Scholar 

  6. K. Polyak, R.A. Weinberg, Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9, 265–273 (2009). https://doi.org/10.1038/nrc2620

  7. I.C. Iser, M.B. Pereira, G. Lenz, M.R. Wink, The epithelial-to-mesenchymal transition-like process in glioblastoma: an updated systematic review and in silico investigation. Med. Res. Rev. 37, 271–313 (2017). https://doi.org/10.1002/med.21408

  8. R. Mahabir, M. Tanino, A. Elmansuri, L. Wang, T. Kimura, T. Itoh, Y. Ohba, H. Nishihara, H. Shirato, M. Tsuda, S. Tanaka, Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma. Neuro. Oncol. 16, 671–685 (2014). https://doi.org/10.1093/neuonc/not239

  9. C.L. Tso, P. Shintaku, J. Chen, Q. Liu, J. Liu, Z. Chen, K. Yoshimoto, P.S. Mischel, T.F. Cloughesy, L.M. Liau, S.F. Nelson, Primary glioblastomas express mesenchymal stem-like properties. Mol. Cancer Res. 4, 607–619 (2006). https://doi.org/10.1158/1541-7786.MCR-06-0005

  10. F. Marcucci, M. Bellone, C.A. Caserta, A. Corti, Pushing tumor cells towards a malignant phenotype: stimuli from the microenvironment, intercellular communications and alternative roads. Int. J. Cancer 135, 1265–1276 (2014). https://doi.org/10.1002/ijc.28572

  11. R. Martinez-Zaguilan, E.A. Seftor, R.E. Seftor, Y.W. Chu, R.J. Gillies, M.J. Hendrix, Acidic pH enhances the invasive behavior of human melanoma cells. Clin. Exp. Metastasis 14, 176–186 (1996)

  12. C. Sahlgren, M.V. Gustafsson, S. Jin, L. Poellinger, U. Lendahl, Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl. Acad. Sci. U. S. A. 105, 6392–6397 (2008). https://doi.org/10.1073/pnas.0802047105

  13. S.A. Mikheeva, A.M. Mikheev, A. Petit, R. Beyer, R.G. Oxford, L. Khorasani, J.P. Maxwell, C.A. Glackin, H. Wakimoto, I. Gonzalez-Herrero, I. Sanchez-Garcia, J.R. Silber, P.J. Horner, R.C. Rostomily, TWIST1 promotes invasion through mesenchymal change in human glioblastoma. Mol. Cancer 9, 194 (2010). https://doi.org/10.1186/1476-4598-9-194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. M. Priester, E. Copanaki, V. Vafaizadeh, S. Hensel, C. Bernreuther, M. Glatzel, V. Seifert, B. Groner, D. Kogel, J. Weissenberger, STAT3 silencing inhibits glioma single cell infiltration and tumor growth. Neuro. Oncol. 15, 840–852 (2013). https://doi.org/10.1093/neuonc/not025

  15. B.B. Aggarwal, Nuclear factor-kappaB: the enemy within. Cancer Cell 6, 203–208 (2004). https://doi.org/10.1016/j.ccr.2004.09.003

  16. B. Chen, J. Liu, T.T. Ho, X. Ding, Y.Y. Mo, ERK-mediated NF-kappaB activation through ASIC1 in response to acidosis. Oncogenesis 5, e279 (2016). https://doi.org/10.1038/oncsis.2016.81

  17. E.R. Fearon, B. Vogelstein, A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990)

  18. R.A. Gatenby, R.J. Gillies, Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891–899 (2004). https://doi.org/10.1038/nrc1478

  19. A. Di Cristofori, S. Ferrero, I. Bertolini, G. Gaudioso, M.V. Russo, V. Berno, M. Vanini, M. Locatelli, M. Zavanone, P. Rampini, T. Vaccari, M. Caroli, V. Vaira, The vacuolar H + ATPase is a novel therapeutic target for glioblastoma. Oncotarget 6, 17514–17531 (2015). https://doi.org/10.18632/oncotarget.4239

  20. A.H. Lee, I.F. Tannock, Heterogeneity of intracellular pH and of mechanisms that regulate intracellular pH in populations of cultured cells. Cancer Res. 58, 1901–1908 (1998)

  21. R. Martinez-Zaguilan, N. Raghunand, R.M. Lynch, W. Bellamy, G.M. Martinez, B. Rojas, D. Smith, W.S. Dalton, R.J. Gillies, pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. Biochem. Pharmacol. 57, 1037–1046 (1999)

  22. N. Robertson, C. Potter, A.L. Harris, Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res. 64, 6160–6165 (2004). https://doi.org/10.1158/0008-5472.CAN-03-2224

  23. C.A. Stedman, M.L. Barclay, Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment. Pharmacol. Ther. 14, 963–978 (2000)

  24. A.B. Thomson, M.D. Sauve, N. Kassam, H. Kamitakahara, Safety of the long-term use of proton pump inhibitors. World J. Gastroenterol. 16, 2323–2330 (2010)

  25. J.M. Shin, G. Sachs, Pharmacology of proton pump inhibitors. Curr. Gastroenterol. Rep. 10, 528–534 (2008)

  26. A. Canitano, E. Iessi, E.P. Spugnini, C. Federici, S. Fais, Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma. Cancer Lett. 376, 278–283 (2016). https://doi.org/10.1016/j.canlet.2016.04.015

  27. T. Song, H.K. Jeon, J.E. Hong, J.J. Choi, T.J. Kim, C.H. Choi, D.S. Bae, B.G. Kim, J.W. Lee, Proton pump inhibition enhances the cytotoxicity of paclitaxel in cervical cancer. Cancer Res. Treat. 49, 595-606 (2017). https://doi.org/10.4143/crt.2016.034

  28. B. Zhang, Y. Yang, X. Shi, W. Liao, M. Chen, A.S. Cheng, H. Yan, C. Fang, S. Zhang, G. Xu, S. Shen, S. Huang, G. Chen, Y. Lv, T. Ling, X. Zhang, L. Wang, Y. Zhuge, X. Zou, Proton pump inhibitor pantoprazole abrogates adriamycin-resistant gastric cancer cell invasiveness via suppression of Akt/GSK-beta/beta-catenin signaling and epithelial-mesenchymal transition. Cancer Lett. 356, 704–712 (2015). https://doi.org/10.1016/j.canlet.2014.10.016

  29. A. Morocutti, M. Merrouche, T. Bjaaland, T. Humphries, M. Mignon, An open-label study of rabeprazole in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion. Aliment. Pharmacol. Ther. 24, 1439–1444 (2006). https://doi.org/10.1111/j.1365-2036.2006.03137.x

  30. D. Pantoflickova, G. Dorta, M. Ravic, P. Jornod, A.L. Blum, Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors. Aliment. Pharmacol. Ther. 17, 1507–1514 (2003)

  31. Y.M. Hu, Q. Mei, X.H. Xu, X.P. Hu, N.Z. Hu, J.M. Xu, Pharmacodynamic and kinetic effect of rabeprazole on serum gastrin level in relation to CYP2C19 polymorphism in Chinese Hans. World J. Gastroenterol. 12, 4750–4753 (2006). https://doi.org/10.3748/wjg.v12.i29.4750

  32. M. Gu, Y. Zhang, X. Zhou, H. Ma, H. Yao, F. Ji, Rabeprazole exhibits antiproliferative effects on human gastric cancer cell lines. Oncol. Lett. 8, 1739–1744 (2014). https://doi.org/10.3892/ol.2014.2354

  33. S. Feng, Z. Zheng, L. Feng, L. Yang, Z. Chen, Y. Lin, Y. Gao, Y. Chen, Proton pump inhibitor pantoprazole inhibits the proliferation, selfrenewal and chemoresistance of gastric cancer stem cells via the EMT/betacatenin pathways. Oncol. Rep. 36, 3207–3214 (2016). https://doi.org/10.3892/or.2016.5154

  34. D.N. Louis, H. Ohgaki, O.D. Wiestler, W.K. Cavenee, P.C. Burger, A. Jouvet, B.W. Scheithauer, P. Kleihues, The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114, 97–109 (2007). https://doi.org/10.1007/s00401-007-0243-4

  35. L. Du, C.S. Lyle, T.B. Obey, W.A. Gaarde, J.A. Muir, B.L. Bennett, T.C. Chambers, Inhibition of cell proliferation and cell cycle progression by specific inhibition of basal JNK activity: evidence that mitotic Bcl-2 phosphorylation is JNK-independent. J. Biol. Chem. 279, 11957–11966 (2004). https://doi.org/10.1074/jbc.M304935200

  36. G.R. Sareddy, K. Geeviman, C. Ramulu, P.P. Babu, The nonsteroidal anti-inflammatory drug celecoxib suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-kappaB pathway. J. Neurooncol. 106, 99–109 (2012). https://doi.org/10.1007/s11060-011-0662-x

  37. T. Azzarito, G. Venturi, A. Cesolini, S. Fais, Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanoma. Cancer Lett. 356, 697–703 (2015). https://doi.org/10.1016/j.canlet.2014.10.017

  38. Y.G. Yeung, E.R. Stanley, A solution for stripping antibodies from polyvinylidene fluoride immunoblots for multiple reprobing. Anal. Biochem. 389, 89–91 (2009). https://doi.org/10.1016/j.ab.2009.03.017

  39. H.M. Smilowitz, J. Weissenberger, J. Weis, J.D. Brown, R.J. O’Neill, J.A. Laissue, Orthotopic transplantation of v-src-expressing glioma cell lines into immunocompetent mice: establishment of a new transplantable in vivo model for malignant glioma. J. Neurosurg. 106, 652–659 (2007). https://doi.org/10.3171/jns.2007.106.4.652

  40. G.J. Gage, D.R. Kipke, W. Shain, Whole animal perfusion fixation for rodents. J. Vis. Exp. 30, 3564 (2012). https://doi.org/10.3791/3564

  41. G.R. Sareddy, M. Panigrahi, S. Challa, A. Mahadevan, P.P. Babu, Activation of Wnt/beta-catenin/Tcf signaling pathway in human astrocytomas. Neurochem. Int. 55, 307–317 (2009). https://doi.org/10.1016/j.neuint.2009.03.016

  42. D.S. Chandrashekar, B. Bashel, S.A.H. Balasubramanya, C.J. Creighton, I. Ponce-Rodriguez, B. Chakravarthi, S. Varambally, UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19, 649–658 (2017). https://doi.org/10.1016/j.neo.2017.05.002

  43. C.W. Li, W. Xia, L. Huo, S.O. Lim, Y. Wu, J.L. Hsu, C.H. Chao, H. Yamaguchi, N.K. Yang, Q. Ding, Y. Wang, Y.J. Lai, A.M. LaBaff, T.J. Wu, B.R. Lin, M.H. Yang, G.N. Hortobagyi, M.C. Hung, Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res. 72, 1290–1300 (2012). https://doi.org/10.1158/0008-5472.CAN-11-3123

  44. S. Ferrari, F. Perut, F. Fagioli, A. Brach Del Prever, C. Meazza, A. Parafioriti, P. Picci, M. Gambarotti, S. Avnet, N. Baldini, S. Fais, Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. J. Transl. Med. 11, 268 (2013). https://doi.org/10.1186/1479-5876-11-268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. C. Happold, P. Roth, W. Wick, N. Schmidt, A.M. Florea, M. Silginer, G. Reifenberger, M. Weller, Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells. J. Neurochem. 122, 444–455 (2012). https://doi.org/10.1111/j.1471-4159.2012.07781.x

  46. T.C. Chou, Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70, 440–446 (2010). https://doi.org/10.1158/0008-5472.CAN-09-1947

  47. D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). https://doi.org/10.1016/j.cell.2011.02.013

  48. I.C. Iser, G. Lenz, M.R. Wink, EMT-like process in glioblastomas and reactive astrocytes. Neurochem. Int. 122, 139–143 (2019). https://doi.org/10.1016/j.neuint.2018.11.016

    Article  CAS  PubMed  Google Scholar 

  49. S. Utsuki, Y. Sato, H. Oka, B. Tsuchiya, S. Suzuki, K. Fujii, Relationship between the expression of E-, N-cadherins and beta-catenin and tumor grade in astrocytomas. J. Neurooncol. 57, 187–192 (2002)

  50. M. Yeo, D.K. Kim, Y.B. Kim, T.Y. Oh, J.E. Lee, S.W. Cho, H.C. Kim, K.B. Hahm, Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells. Clin. Cancer Res. 10, 8687–8696 (2004). https://doi.org/10.1158/1078-0432.CCR-04-1065

  51. S. Zhang, Y. Wang, S.J. Li, Lansoprazole induces apoptosis of breast cancer cells through inhibition of intracellular proton extrusion. Biochem. Biophys. Res. Commun. 448, 424–429 (2014). https://doi.org/10.1016/j.bbrc.2014.04.127

  52. K. Geeviman, D. Babu, P. Prakash Babu, Pantoprazole Induces Mitochondrial Apoptosis and Attenuates NF-kappaB Signaling in Glioma Cells. Cell. Mol. Neurobiol. 38(8), 1491–1504 (2018). https://doi.org/10.1007/s10571-018-0623-4

    Article  CAS  PubMed  Google Scholar 

  53. P. Breedveld, J.H. Beijnen, J.H. Schellens, Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol. Sci. 27(1), 17–24 (2006). https://doi.org/10.1016/j.tips.2005.11.009

    Article  CAS  PubMed  Google Scholar 

  54. A. De Milito, R. Canese, M.L. Marino, M. Borghi, M. Iero, A. Villa, G. Venturi, F. Lozupone, E. Iessi, M. Logozzi, P. Della Mina, M. Santinami, M. Rodolfo, F. Podo, L. Rivoltini, S. Fais, pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int. J. Cancer 127, 207–219 (2010). https://doi.org/10.1002/ijc.25009

  55. R.E. Kast, N. Skuli, G. Karpel-Massler, G. Frosina, T. Ryken, M.E. Halatsch, Blocking epithelial-to-mesenchymal transition in glioblastoma with a sextet of repurposed drugs: the EIS regimen. Oncotarget 8, 60727–60749 (2017). https://doi.org/10.18632/oncotarget.18337

  56. J.P. Thiery, Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002). https://doi.org/10.1038/nrc822

  57. R.E. Bachelder, S.O. Yoon, C. Franci, A.G. de Herreros, A.M. Mercurio, Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J. Cell Biol. 168, 29–33 (2005). https://doi.org/10.1083/jcb.200409067

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Acknowledgements

We thank Dr. Chintal Ramulu for his assistance in the animal experiments.

Funding

The authors acknowledge the financial support of the Department of Science and Technology (DST- India), CSRI (Grant No. SR/CSRI/196/2016), Science & Engineering Research Board (SERB)(Grant No. CRG/2020/005021, and the Department of Biotechnology (DBT-India) (Grant No. BT/PR18168/MED/29/1064/2016. The authors also thank DST- FIST and UGC-SAP of the DoBB. DB thanks the Department of Biotechnology-India for a student fellowship (Award no: DBT/2013/UOH/79). AM acknowledges funding from DST-Women scientist- A (Grant No. SR/WOS-A/CS-31/2019(G)

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Authors and Affiliations

  1. Neuro Science Laboratory, Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, 500 046, Telangana State, India

    Deepak Babu, Anwita Mudiraj, Neera Yadav & Phanithi Prakash Babu

  2. Department of Neurosurgery, Krishna Institute of Medical Sciences (KIMS), 500 003, Secunderabad, Telangana State, India

    Chandrashekhar Y.B.V.K. & Manas Panigrahi

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Contributions

DB and PPB made hypothesis. DB, AM and NY performed all cell-based experiments. DB performed the animal experiments. DB, AM, NY, ChYBVK, MP and PPB analyzed the data. Patient samples from the Department of Neurosurgery, Krishna Institute of Medical Sciences (KIMS) were collected and analyzed by DB, ChYBVK and MP. DB and AM wrote the original draft of the manuscript. DB, AM, NY, ChYBVK, MP and PPB critically reviewed the manuscript and approved its submission.

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Correspondence to Phanithi Prakash Babu.

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The Institutional Ethics Committee (IEC) (reference number UH/IEC/2016/180) and Institutional Animal Ethics Committee (IAEC) (reference number UH/IAEC/PPB/2017-I/P7), University of Hyderabad, Hyderabad (500 046) approved all procedures involving human tissue and animal-related experiments.

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Babu, D., Mudiraj, A., Yadav, N. et al. Rabeprazole has efficacy per se and reduces resistance to temozolomide in glioma via EMT inhibition. Cell Oncol. 44, 889–905 (2021). https://doi.org/10.1007/s13402-021-00609-w

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