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Hypoxic conditions increases H2S-induced ER stress in A2870 cells

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Abstract

Hypoxia—a state of lower oxygen demand—is responsible for a higher aggressiveness of tumors and therefore a worse prognosis. During hypoxia, several metabolic pathways are re-organized, e.g., energetic metabolism, modulation of pH, and calcium transport. Calcium is an important second messenger that regulates variety of processes in the cell. Thus, aim of this work was to compare H2S modulation of the intracellular calcium transport systems in hypoxia and in cells grown in standard culture conditions. For all experiments, we used ovarian cancer cell line (A2780). H2S is a novel gasotransmitter, known to be involved in a modulation of several calcium transport systems, thus resulting in altered calcium signaling. Two models of hypoxia were used in our study—chemical (induced by dimethyloxallyl glycine) and 2 % O2 hypoxia, both combined with a treatment using a slow H2S donor GYY4137. In hypoxia, we observed rapid changes in cytosolic and reticular calcium levels compared to cells grown in standard culture conditions, and these changes were even more exagerrated when combined with the GYY4137. Changes in a calcium homeostasis result from IP3 receptor´s up-regulation and down-regulation of the SERCA 2, which leads to a development of the endoplasmic reticulum stress. Based on our results, we propose a higher vulnerability of calcium transport systems to H2S regulation under hypoxia.

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References

  1. Akl H, Bultynck G (2013) Altered Ca2+ signaling in cancer cells: proto-oncogenes and tumor suppressors targeting IP3 receptors. Biochim Biophys Acta 1835:180–193

    CAS  PubMed  Google Scholar 

  2. Bergner A, Kellner J, Tufman A, Huber RM (2009) Endoplasmic reticulum Ca2+-homeostasis is altered in small and non-small cell lung cancer cell lines. J Exp Clin Cancer Res 28:25. doi:10.1186/1756-9966-28-25

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wang JY, Chen BK, Wang YS, Tsai YT, Chen WCH, Chang WCH, Hou MF, Wu ICH, Chang WCH (2011) Involvement of store-operated calcium signaling in EGF-mediated COX-2 gene activation in cancer cells. Cell Signal. doi:10.1016/j.Cellsig.08.017

    Google Scholar 

  4. Bredoux R, Enouf J, Papp B (2002) Expression of endomembrane calcium pumps in colon and gastric cancer cells. Induction of SERCA3 expression during differentiation. J Biol Chem 277:26310–26320

    Article  PubMed  Google Scholar 

  5. Pacifico F, Ulianich L, De Micheli S, Treglia S, Leonardi A, Vito P, Formisano S, Consiglio E, Di Jeso B (2003) The expression of the sarco/endoplasmic reticulum Ca2+-ATPases in thyroid and its down-regulation following neoplastic transformation. J Mol Endocrinol 30:399–409

    Article  CAS  PubMed  Google Scholar 

  6. Ghosh S, Adhikary A, Chakraborty S, Nandi P, Mohanty S, Chakraborty S, Bhattacharjee P, Mukherjee S, Putatunda S, Chakraborty S, Chakraborty A, Sa G, Das T, Sen PC (2012) Nifetepimine, a dihydropyrimidone, ensures CD4 T cell survival in a tumor microenvironment by Maneuvering Sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). J Biol Chem 287:32881–32896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Krizanova O, Markova J, Pacak K, Skultety L, Soltysova A, Hudecova S (2014) Triptolide induces apoptosis through the SERCA 3 upregulation in PC12 cells. Gen Physiol Biophys 33:137–144

    Article  CAS  PubMed  Google Scholar 

  8. Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival And cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442

    Article  CAS  PubMed  Google Scholar 

  9. Bonnefoy-Berard N, Aouacheria A, Verschelde C, Quemeneur L, Marcais A, Marvel J (2004) Control of proliferation by Bcl-2 family members. Biochim Biophys Acta (BBA) Mol Cell Res 1644:159–168

    Article  CAS  Google Scholar 

  10. Akl H, Vervloessem T, Kiviluoto S, Bittremieux M, Parys JB, De Smedt H, Bultynck G (2014) A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum. Biochim Biophys Acta 1843:2240–2252

    Article  CAS  PubMed  Google Scholar 

  11. Zhong F, Harr MW, Bultynck G, Monaco G, Parys JB, De Smedt H, Rong YP, Molitoris JK, Lam M, Ryder Ch, Matsuyama S, Distelhorst CW (2011) Induction of Ca2-driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2–IP3 receptor interaction. Blood 117:2924–2934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hedgepeth SC, Garcia MI, Wagner LE II, Rodriguez AM, Chintapalli SV, Snyder RR, Hankins GDV, Henderson BR, Brodie KM, Yule DI, van Rossum DB, Boehning D (2015) The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release. J Biol Chem. doi:10.1074/jbc.M114.611186

    PubMed  Google Scholar 

  13. Castro-Piedras I, Perez-Zoghbi JF (2013) Hydrogen sulphide inhibits Ca2+ release through InsP3 receptors and relaxes airway smooth muscle. J Physiol 591:5999–6015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kloesch B, Steiner G, Mayer B, Schmidt K (2015) Hydrogen sulfide inhibits endothelial nitric oxide formation and receptor ligand-mediated Ca2+ release in endothelial and smooth muscle cells. Pharmacol Rep. doi:10.1016/j.pharep.05.026

    PubMed  Google Scholar 

  15. Lencesova L, Hudecova S, Csaderova L, Markova J, Soltysova A, Pastorek M, Sedlak J, Wood ME, Whiteman M, Ondrias K, Krizanova O (2013) Sulphide signalling potentiates apoptosis through the up-regulation of IP3 receptor types 1 and 2. Acta Physiol (Oxf) 208:350–361

    Article  CAS  Google Scholar 

  16. Lee ZW, Teo XY, Tay EY, Tan CH, Hagen T, Moore PK, Deng LW (2014) Utilizing Hydrogensulfide as a novel anti-cancer agent by targeting cancer glycolysis and Ph imbalance. Br J Pharmacol 171:4322–4336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lahiri S, Roy A, Li J, Mokashi A, Baby SM (2003) Ca2+ responses to hypoxia are mediated by IP3-R on Ca2+ store depletion. Adv Exp Med Biol 536:25–32

    Article  CAS  PubMed  Google Scholar 

  18. Jurkovicova D, Sedlakova B, Lacinova L, Kopacek J, Sulova Z, Sedlak J, Krizanova O (2008) Hypoxia differently modulates gene expression of inositol 1,4,5-trisphosphate receptors in mouse kidney and HEK 293 cell line. Ann N Y Acad Sci 1148:421–427. doi:10.1196/annals.1410.034

    Article  CAS  PubMed  Google Scholar 

  19. Zimna A, Kurpisz M (2015) Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. Biomed Res Int. doi:10.1155/2015/549412

    PubMed  PubMed Central  Google Scholar 

  20. Jochmanová I, Zhuang Z, Pacak K (2015) Pheochromocytoma: gasping for Air. Horm Cancer. doi:10.1007/s12672-015-0231-4

    PubMed  Google Scholar 

  21. Wu B, Teng H, Yang G, Wu L, Wang R (2012) Hydrogen sulfide inhibits the translational expression of hypoxia-inducible factor-1α. Br J Pharmacol 167:1492–1505. doi:10.1111/j.1476-5381.2012.02113.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with The Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  23. Jakubikova J, Cervi D, Ooi M, Kim K, Nahar S, Klippel S, Cholujova D, Leiba M, Daley JF, Delmore J, Negri J, Blotta S, McMillin DW, Hideshima T, Richardson PG, Sedlak J, Anderson KC, Mitsiades CS (2011) Anti-tumor activity and signaling events triggered by the isothiocyanates, sulforaphane and phenethyl isothiocyanate, in multiple myeloma. Haematologica 96:1170–1179. doi:10.3324/haematol.2010.029363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jiang W, Huang Y, Wang JP, Yu XY, Zhang LY (2013) The synergistic anticancer effect of artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo. Asian Pac J Cancer Prev 14:4615–4619

    Article  PubMed  Google Scholar 

  25. Pastorek M, Simko V, Takacova M, Barathova M, Bartosova M, Hunakova L, Sedlakova O, Hudecova S, Krizanova O, Dequiedt F, Pastorekova S, Sedlak J (2015) Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy. Int J Oncol. doi:10.3892/ijo.2015.2987

    PubMed  PubMed Central  Google Scholar 

  26. Li L, Rose P, Moore PK (2011) Hydrogen sulfide and cell signaling. Annu Rev Pharmacol Toxicol 51:169–187

    Article  CAS  PubMed  Google Scholar 

  27. Li L, Whiteman M, Guan YY, Neo KL, Cheng Y et al (2008) Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 117:2351–2360

    Article  CAS  PubMed  Google Scholar 

  28. Lee ZW, Zhou J, Chen C-S, Zhao Y, Tan C-H et al (2011) The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo. PLoS ONE 6(6):e21077. doi:10.1371/journal.pone.0021077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang R (2012) Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 92:791–896

    Article  CAS  PubMed  Google Scholar 

  30. Zhang W, Xu C, Yang G, Wu L, Wang R (2015) Interaction of H2S with calcium permeable channels and transporters. Oxid Med Cell Longev. doi:10.1155/2015/323269

    Google Scholar 

  31. Akl H, Bultynck G (2013) Altered Ca2+ signaling in cancer cells: proto-oncogenes and tumor suppressors targeting IP3 receptors. Biochim Biophys Acta 1835:180–193

    CAS  PubMed  Google Scholar 

  32. Szatkowski C, Parys JB, Ouadid-Ahidouch H, Matifat F (2010) Inositol 1,4,5-trisphosphate- induced Ca2+ signalling is involved in estradiol-induced breast cancer epithelial cell growth. Mol Cancer 9:156

    Article  PubMed  PubMed Central  Google Scholar 

  33. Shibao K, Fiedler MJ, Nagata J, Minagawa N, Hirata K et al (2010) The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma. Cell Calcium 48:315–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Estrela JM, Ortega A, Obrador E (2006) Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci 43:143–181

    Article  CAS  PubMed  Google Scholar 

  35. Ning S, Sekar TV, Scicinski J, Oronsky B, Peehl DM, Knox SJ, Paulmurugan R (2015) Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent. Oncotarget 6:2154–21556

    Article  Google Scholar 

  36. Zhang C, Han Y, Huang H, Qu L, Shou C (2014) High NR2F2 transcript level is associated with increased survival and its expression inhibits TGF-β-dependent epithelial-mesenchymal transition in breast cancer. Breast Cancer Res Treat 147:265–281

    Article  CAS  PubMed  Google Scholar 

  37. Safe S, Jin UH, Hedrick E, Reeder A, Lee SO (2013) Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol 28:157–172

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants APVV-14-0351, APVV-0045-11, and VEGA 2/0082/16.

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Authors and Affiliations

  1. Biomedical Research Center, Institute for Clinical and Translational Research, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovak Republic

    Lubomira Lencesova, Miroslav Vlcek, Olga Krizanova & Sona Hudecova

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  1. Lubomira Lencesova
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  2. Miroslav Vlcek
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  3. Olga Krizanova
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Correspondence to Sona Hudecova.

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Lencesova, L., Vlcek, M., Krizanova, O. et al. Hypoxic conditions increases H2S-induced ER stress in A2870 cells. Mol Cell Biochem 414, 67–76 (2016). https://doi.org/10.1007/s11010-016-2659-4

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  • DOI: https://doi.org/10.1007/s11010-016-2659-4

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