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Apoptosis

, Volume 22, Issue 6, pp 816–826 | Cite as

Anandamide oxidative metabolism-induced endoplasmic reticulum stress and apoptosis

  • M. Almada
  • B. M. Fonseca
  • C. Amaral
  • M. Diniz-da-Costa
  • G. Correia-da-Silva
  • N. Teixeira
Article

Abstract

The Endocannabinoid System (ECS) has been recognized as a crucial player in human reproduction. Changes in the levels of anandamide (AEA), the main endocannabinoid (eCB), negatively affect reproductive events, such as implantation, decidualization and placentation. Cyclooxygenase-2 (COX-2) is a major enzyme expressed in the endometrium and its involvement in female reproductive system has evolved over the last few years. Currently, COX-2 oxidative metabolism is emerging as a key mediator of AEA-induced actions. In this study, we aimed to disclose the mechanisms underlying the effects of AEA in human endometrial stromal cell fate, using a human-derived endometrial cell line (St-T1b). We found that AEA has an anti-proliferative activity through a direct effect on cell cycle progression by inducing G2/M arrest. Moreover, high levels of AEA increased COX-2 activity, triggering apoptotic cell death, with loss of mitochondrial membrane potential, induction of caspase -9 and -3/-7 activities, and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, the involvement of intracellular reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress was verified. These effects were prevented by pre-incubation with a selective COX-2 inhibitor. Therefore, we hypothesize that, in response to altered levels of this eCB, COX-2 oxidative metabolism of AEA may deregulate endometrial cell turnover and, consequently, interfere with cellular events crucial for implantation and decidualization, with a negative impact on human fertility.

Keywords

Anandamide Apoptosis Human endometrial stromal cells 

Notes

Acknowledgements

The authors thank Fundação para a Ciência e Tecnologia (FCT) for the grant attributed to Almada M (SFRH/BD/81561/2011), Fonseca BM (SFRH/BPD/72958/2010) and Cristina Amaral (SFRH/BPD/98304/2013). The authors also thank to Joana Macedo for helping with the graphic design.

References

  1. 1.
    Gellersen B, Brosens IA, Brosens JJ (2007) Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med 25(6):445–453. doi: 10.1055/s-2007-991042 CrossRefPubMedGoogle Scholar
  2. 2.
    Dahmoun M, Boman K, Cajander S, Westin P, Backstrom T (1999) Apoptosis, proliferation, and sex hormone receptors in superficial parts of human endometrium at the end of the secretory phase. J Clin Endocrinol Metab 84(5):1737–1743. doi: 10.1210/jcem.84.5.5706 PubMedGoogle Scholar
  3. 3.
    Tao XJ, Tilly KI, Maravei DV, Shifren JL, Krajewski S, Reed JC, Tilly JL, Isaacson KB (1997) Differential expression of members of the bcl-2 gene family in proliferative and secretory human endometrium: glandular epithelial cell apoptosis is associated with increased expression of bax. J Clin Endocrinol Metab 82(8):2738–2746. doi: 10.1210/jcem.82.8.4146 PubMedGoogle Scholar
  4. 4.
    Kokawa K, Shikone T, Nakano R (1996) Apoptosis in the human uterine endometrium during the menstrual cycle. J Clin Endocrinol Metab 81(11):4144–4147. doi: 10.1210/jcem.81.11.8923873 PubMedGoogle Scholar
  5. 5.
    Maccarrone M (2015) Endocannabinoid signaling in female reproductive events: a potential therapeutic target? Expert Opin Ther Targets 19(11):1423–1427. doi: 10.1517/14728222.2015.1062878 CrossRefPubMedGoogle Scholar
  6. 6.
    Fonseca BM, Costa MA, Almada M, Correia-da-Silva G, Teixeira NA (2013) Endogenous cannabinoids revisited: a biochemistry perspective. Prostaglandins Other Lipid Mediat 102–103:13–30. doi: 10.1016/j.prostaglandins.2013.02.002 CrossRefPubMedGoogle Scholar
  7. 7.
    Urquhart P, Nicolaou A, Woodward DF (2015) Endocannabinoids and their oxygenation by cyclo-oxygenases, lipoxygenases and other oxygenases. Biochim Biophys Acta 1851(4):366–376. doi: 10.1016/j.bbalip.2014.12.015 CrossRefPubMedGoogle Scholar
  8. 8.
    Di Marzo V, De Petrocellis L (2010) Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem 17(14):1430–1449CrossRefPubMedGoogle Scholar
  9. 9.
    Pistis M, Melis M (2010) From surface to nuclear receptors: the endocannabinoid family extends its assets. Curr Med Chem 17(14):1450–1467CrossRefPubMedGoogle Scholar
  10. 10.
    McFarland MJ, Barker EL (2005) Lipid rafts: a nexus for endocannabinoid signaling? Life Sci 77(14):1640–1650. doi: 10.1016/j.lfs.2005.05.010 CrossRefPubMedGoogle Scholar
  11. 11.
    Fonseca BM, Correia-da-Silva G, Teixeira NA (2013) The endocannabinoid anandamide induces apoptosis of rat decidual cells through a mechanism involving ceramide synthesis and p38 MAPK activation. Apoptosis 18(12):1526–1535. doi: 10.1007/s10495-013-0892-9 CrossRefPubMedGoogle Scholar
  12. 12.
    Fonseca BM, Correia-da-Silva G, Teixeira NA (2009) Anandamide-induced cell death: dual effects in primary rat decidual cell cultures. Placenta 30(8):686–692. doi: 10.1016/j.placenta.2009.05.012 CrossRefPubMedGoogle Scholar
  13. 13.
    Costa MA, Fonseca BM, Keating E, Teixeira NA, Correia-da-Silva G (2014) Transient receptor potential vanilloid 1 is expressed in human cytotrophoblasts: induction of cell apoptosis and impairment of syncytialization. Int J Biochem Cell Biol 57:177–185. doi: 10.1016/j.biocel.2014.10.008 CrossRefPubMedGoogle Scholar
  14. 14.
    Giuliano M, Calvaruso G, Pellerito O, Portanova P, Carlisi D, Vento R, Tesoriere G (2006) Anandamide-induced apoptosis in Chang liver cells involves ceramide and JNK/AP-1 pathway. Int J Mol Med 17(5):811–819PubMedGoogle Scholar
  15. 15.
    DeMorrow S, Glaser S, Francis H, Venter J, Vaculin B, Vaculin S, Alpini G (2007) Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts. J Biol Chem 282(17):13098–13113. doi: 10.1074/jbc.M608238200 CrossRefPubMedGoogle Scholar
  16. 16.
    Costa MA, Fonseca BM, Teixeira NA, Correia-da-Silva G (2015) The endocannabinoid anandamide induces apoptosis in cytotrophoblast cells: involvement of both mitochondrial and death receptor pathways. Placenta 36(1):69–76. doi: 10.1016/j.placenta.2014.10.011 CrossRefPubMedGoogle Scholar
  17. 17.
    Almada M, Piscitelli F, Fonseca BM, Di Marzo V, Correia-da-Silva G, Teixeira N (2015) Anandamide and decidual remodelling: COX-2 oxidative metabolism as a key regulator. Biochim Biophys Acta 1851(11):1473–1481. doi: 10.1016/j.bbalip.2015.08.011 CrossRefPubMedGoogle Scholar
  18. 18.
    Patsos HA, Greenhough A, Hicks DJ, Al Kharusi M, Collard TJ, Lane JD, Paraskeva C, Williams AC (2010) The endogenous cannabinoid, anandamide, induces COX-2-dependent cell death in apoptosis-resistant colon cancer cells. Int J Oncol 37(1):187–193PubMedGoogle Scholar
  19. 19.
    Soliman E, Henderson KL, Danell AS, Van Dross R (2016) Arachidonoyl-ethanolamide activates endoplasmic reticulum stress-apoptosis in tumorigenic keratinocytes: role of cyclooxygenase-2 and novel J-series prostamides. Mol Carcinog 55(2):117–130. doi: 10.1002/mc.22257 CrossRefPubMedGoogle Scholar
  20. 20.
    El-Talatini MR, Taylor AH, Konje JC (2010) The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle. Fertil Steril 93(6):1989–1996. doi: 10.1016/j.fertnstert.2008.12.033 CrossRefPubMedGoogle Scholar
  21. 21.
    Richards RG, Brar AK, Frank GR, Hartman SM, Jikihara H (1995) Fibroblast cells from term human decidua closely resemble endometrial stromal cells: induction of prolactin and insulin-like growth factor binding protein-1 expression. Biol Reprod 52(3):609–615CrossRefPubMedGoogle Scholar
  22. 22.
    Olivares EG, Montes MJ, Oliver C, Galindo JA, Ruiz C (1997) Cultured human decidual stromal cells express B7-1 (CD80) and B7-2 (CD86) and stimulate allogeneic T cells. Biol Reprod 57(3):609–615CrossRefPubMedGoogle Scholar
  23. 23.
    Samalecos A, Reimann K, Wittmann S, Schulte HM, Brosens JJ, Bamberger AM, Gellersen B (2009) Characterization of a novel telomerase-immortalized human endometrial stromal cell line, St-T1b. Reprod Biol Endocrinol 7:76. doi: 10.1186/1477-7827-7-76 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Almada M, Amaral C, Diniz-da-Costa M, Correia-da-Silva G, Teixeira NA, Fonseca BM (2016) The endocannabinoid anandamide impairs in vitro decidualization of human cells. Reproduction 152(4):351–361. doi: 10.1530/REP-16-0364 CrossRefPubMedGoogle Scholar
  25. 25.
    Li G, Xia M, Abais JM, Boini K, Li PL, Ritter JK (2016) Protective action of anandamide and Its COX-2 metabolite against l-homocysteine-induced NLRP3 inflammasome activation and injury in podocytes. J Pharmacol Exp Ther 358(1):61–70. doi: 10.1124/jpet.116.233239 CrossRefPubMedGoogle Scholar
  26. 26.
    Sordelli MS, Beltrame JS, Cella M, Franchi AM, Ribeiro ML (2012) Cyclooxygenase-2 prostaglandins mediate anandamide-inhibitory action on nitric oxide synthase activity in the receptive rat uterus. Eur J Pharmacol 685(1–3):174–179. doi: 10.1016/j.ejphar.2012.04.034 CrossRefPubMedGoogle Scholar
  27. 27.
    Amaral C, Borges M, Melo S, da Silva ET, Correia-da-Silva G, Teixeira N (2012) Apoptosis and autophagy in breast cancer cells following exemestane treatment. PloS One 7(8):e42398. doi: 10.1371/journal.pone.0042398 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Xie C, Liu G, Liu J, Huang Z, Wang F, Lei X, Wu X, Huang S, Zhong D, Xu X (2012) Anti-proliferative effects of anandamide in human hepatocellular carcinoma cells. Oncol Lett 4(3):403–407. doi: 10.3892/ol.2012.751 PubMedPubMedCentralGoogle Scholar
  29. 29.
    De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M, Di Marzo V (1998) The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci USA 95(14):8375–8380CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Orellana-Serradell O, Poblete CE, Sanchez C, Castellon EA, Gallegos I, Huidobro C, Llanos MN, Contreras HR (2015) Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep 33(4):1599–1608. doi: 10.3892/or.2015.3746 PubMedPubMedCentralGoogle Scholar
  31. 31.
    Melck D, Rueda D, Galve-Roperh I, De Petrocellis L, Guzman M, Di Marzo V (1999) Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells. FEBS Lett 463(3):235–240CrossRefPubMedGoogle Scholar
  32. 32.
    Hamtiaux L, Hansoulle L, Dauguet N, Muccioli GG, Gallez B, Lambert DM (2011) Increasing antiproliferative properties of endocannabinoids in N1E-115 neuroblastoma cells through inhibition of their metabolism. PloS One 6(10):e26823. doi: 10.1371/journal.pone.0026823 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Jiang Y, Miyazaki T, Honda A, Hirayama T, Yoshida S, Tanaka N, Matsuzaki Y (2005) Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone. J Gastroenterol 40(5):490–497. doi: 10.1007/s00535-005-1574-3 CrossRefPubMedGoogle Scholar
  34. 34.
    Patsos HA, Hicks DJ, Dobson RR, Greenhough A, Woodman N, Lane JD, Williams AC, Paraskeva C (2005) The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2. Gut 54(12):1741–1750. doi: 10.1136/gut.2005.073403 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Nunn A, Guy G, Bell JD (2012) Endocannabinoids in neuroendopsychology: multiphasic control of mitochondrial function. Philosophical transactions of the Royal Society of London Series B. Biol Sci 367(1607):3342–3352. doi: 10.1098/rstb.2011.0393 CrossRefGoogle Scholar
  36. 36.
    Soliman E, Van Dross R (2015) Anandamide-induced endoplasmic reticulum stress and apoptosis are mediated by oxidative stress in non-melanoma skin cancer: receptor-independent endocannabinoid signaling. Mol Carcinog. doi: 10.1002/mc.22429 Google Scholar
  37. 37.
    Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9(12):2277–2293. doi: 10.1089/ars.2007.1782 CrossRefPubMedGoogle Scholar
  38. 38.
    Murphy MP (2013) Mitochondrial dysfunction indirectly elevates ROS production by the endoplasmic reticulum. Cell Metab 18(2):145–146. doi: 10.1016/j.cmet.2013.07.006 CrossRefPubMedGoogle Scholar
  39. 39.
    Fang C, Zhang J, Qi D, Fan X, Luo J, Liu L, Tan Q (2014) Evodiamine induces G2/M arrest and apoptosis via mitochondrial and endoplasmic reticulum pathways in H446 and H1688 human small-cell lung cancer cells. PloS One 9(12):e115204. doi: 10.1371/journal.pone.0115204 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kim R, Emi M, Tanabe K, Murakami S (2006) Role of the unfolded protein response in cell death. Apoptosis 11(1):5–13. doi: 10.1007/s10495-005-3088-0 CrossRefPubMedGoogle Scholar
  41. 41.
    Jeon MJ, Leem J, Ko MS, Jang JE, Park HS, Kim HS, Kim M, Kim EH, Yoo HJ, Lee CH, Park IS, Lee KU, Koh EH (2012) Mitochondrial dysfunction and activation of iNOS are responsible for the palmitate-induced decrease in adiponectin synthesis in 3T3L1 adipocytes. Exp Mol Med 44(9):562–570. doi: 10.3858/emm.2012.44.9.064 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Boelens J, Lust S, Offner F, Bracke ME, Vanhoecke BW (2007) Review. The endoplasmic reticulum: a target for new anticancer drugs. In vivo 21(2):215–226PubMedGoogle Scholar
  43. 43.
    Pasquariello N, Catanzaro G, Marzano V, Amadio D, Barcaroli D, Oddi S, Federici G, Urbani A, Finazzi Agro A, Maccarrone M (2009) Characterization of the endocannabinoid system in human neuronal cells and proteomic analysis of anandamide-induced apoptosis. J Biol Chem 284(43):29413–29426. doi: 10.1074/jbc.M109.044412 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lim MP, Devi LA, Rozenfeld R (2011) Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. Cell Death Dis 2:e170. doi: 10.1038/cddis.2011.52 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hasanain M, Bhattacharjee A, Pandey P, Ashraf R, Singh N, Sharma S, Vishwakarma AL, Datta D, Mitra K, Sarkar J (2015) Alpha-solanine induces ROS-mediated autophagy through activation of endoplasmic reticulum stress and inhibition of Akt/mTOR pathway. Cell Death Dis 6:e1860. doi: 10.1038/cddis.2015.219 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hu CJ, Xu MZ, Qin RJ, Chen WF, Xu X (2015) Wogonin induces apoptosis and endoplasmic reticulum stress in HL-60 leukemia cells through inhibition of the PI3K-AKT signaling pathway. Oncol Rep 33(6):3146–3154. doi: 10.3892/or.2015.3896 PubMedGoogle Scholar
  47. 47.
    Paixao J, Dinis TC, Almeida LM (2011) Dietary anthocyanins protect endothelial cells against peroxynitrite-induced mitochondrial apoptosis pathway and Bax nuclear translocation: an in vitro approach. Apoptosis 16(10):976–989. doi: 10.1007/s10495-011-0632-y CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • M. Almada
    • 1
  • B. M. Fonseca
    • 1
  • C. Amaral
    • 1
  • M. Diniz-da-Costa
    • 1
  • G. Correia-da-Silva
    • 1
  • N. Teixeira
    • 1
  1. 1.UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal

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