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Inhibition of secretory phospholipase A2 IIa attenuates prostaglandin E2-induced invasiveness in lung adenocarcinoma

  • Alison L. HalpernEmail author
  • Patrick D. Kohtz
  • Jessica Y. Rove
  • Lihua Ao
  • Xianzhong Meng
  • David A. Fullerton
  • Michael J. Weyant
Article
  • 31 Downloads

Abstract

Secretory phospholipase A2 IIa (sPLA2 IIa) catalyzes the production of multiple inflammatory mediators that influence the development of lung and other cancers. The most potent of these carcinogenic mediators is prostaglandin E2 (PGE2). We hypothesize that sPLA2 IIa inhibition modulates the production of PGE2, and sPLA2 IIa inhibition exerts its antineoplastic effects via downregulation of PGE2 production. We aim to evaluate these relationships via analysis of PGE2-mediated growth regulation pathways. A549 and H1650 lung adenocarcinoma cells were assayed for PGE2 production in the presence of sPLA2 IIa inhibitor. A549 and H1650 cells were treated with PGE2 and immune blotting was performed to assess ICAM-1 expression and STAT-3 activity. PGE2-induced ICAM-1 expression was measured via immunofluorescence. A549 and H1650 cells were treated with PGE2 in the presence of STAT3 inhibitor and assayed for ICAM-1 expression. A549 cells were treated with PGE2 in the presence ICAM-1 blocking antibody and assayed for invasion. PGE2 stimulation significantly increased the invasiveness and proliferation of lung adenocarcinoma (invasion p < 0.05, proliferation p < 0.05 A549 cells, p < 0.005 H1650 cells). sPLA2 IIa inhibition reduced PGE2 secretion (p < 0.05). PGE2 stimulation significantly upregulated the expression of cell adhesion molecule ICAM-1 and the phosphorylation of anti-apoptotic transcription factor STAT3 (p < 0.05). STAT3 inhibition attenuated ICAM-1 expression demonstrating the dependence of ICAM-1 on the STAT3 pathway (p < 0.05). ICAM-1 blockade attenuated the pro-invasive effects of PGE2 (p < 0.05). sPLA2 IIa inhibition attenuates the potent effects of PGE2-induced invasiveness. This is mediated by decreasing pro-inflammatory and invasion-promoting ICAM-1via the STAT-3 pathway. These data further describe how sPLA2 IIa inhibition mechanistically exerts its anticancer effects and support its use as an antineoplastic agent.

Keywords

Lung cancer Invasion Cell signaling sPLA2 Prostaglandin 

Notes

Acknowledgements

We would like to acknowledge the University of Colorado Department of Surgery, Division of Cardiothoracic Surgery for assistance in performing this research.

Funding

This work was funded by the Department of Surgery, Division of Cardiothoracic Surgery, and there is no outside funding or grants to report.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest related to this work.

References

  1. 1.
    Gomes M, Teixeira AL, Coelho A, Araújo A, Medeiros R (2014) The role of inflammation in lung cancer. In: Aggarwal BB, Sung B, Gupta SC (eds) Inflammation and cancer. Springer, Basel, pp 1–23.  https://doi.org/10.1007/978-3-0348-0837-8_1 Google Scholar
  2. 2.
    Aggarwal BB, Vijayalekshmi RV, Sung B (2009) Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 15(2):425.  https://doi.org/10.1158/1078-0432.CCR-08-0149 CrossRefGoogle Scholar
  3. 3.
    Bennett DT, Deng X-S, Yu JA, Bell MT, Mauchley DC, Meng X, Reece TB, Fullerton DA, Weyant MJ (2014) Cancer stem cell phenotype is supported by secretory phospholipase A2 in human lung cancer cells. Ann Thorac Surg 98(2):439–446.  https://doi.org/10.1016/j.athoracsur.2014.04.044 CrossRefGoogle Scholar
  4. 4.
    Brglez V, Lambeau G, Petan T (2014) Secreted phospholipases A2 in cancer: diverse mechanisms of action. Biochimie 107(Pt A):114–123.  https://doi.org/10.1016/j.biochi.2014.09.023 CrossRefGoogle Scholar
  5. 5.
    Dong Z, Liu Y, Scott KF, Levin L, Gaitonde K, Bracken RB, Burke B, Zhai QJ, Wang J, Oleksowicz L, Lu S (2010) Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer. Carcinogenesis 31(11):1948–1955.  https://doi.org/10.1093/carcin/bgq188 CrossRefGoogle Scholar
  6. 6.
    Dong Z, Meller J, Succop P, Wang J, Wikenheiser-Brokamp K, Starnes S, Lu S (2014) Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells. Int J Oncol 45(3):978–984.  https://doi.org/10.3892/ijo.2014.2486 CrossRefGoogle Scholar
  7. 7.
    Kupert E, Anderson M, Liu Y, Succop P, Levin L, Wang J, Wikenheiser-brokamp K, Chen P, Pinney SM, Macdonald T, Dong Z, Starnes S, Lu S (2011) Plasma secretory phospholipase A2-IIa as a potential biomarker for lung cancer in patients with solitary pulmonary nodules. BMC Cancer 11:513.  https://doi.org/10.1186/1471-2407-11-513 CrossRefGoogle Scholar
  8. 8.
    Oleksowicz L, Liu Y, Bracken RB, Gaitonde K, Burke B, Succop P, Levin L, Dong Z, Lu S (2012) Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer. Prostate 72(10):1140–1149.  https://doi.org/10.1002/pros.22463 CrossRefGoogle Scholar
  9. 9.
    Wang M, Hao FY, Wang JG, Xiao W (2014) Group IIa secretory phospholipase A2 (sPLA2IIa) and progression in patients with lung cancer. Eur Rev Med Pharmacol Sci 18(18):2648–2654Google Scholar
  10. 10.
    Kuwata H, Sawada H, Murakami M, Kudo I (1999) Role of type IIA secretory phospholipase A2 in arachidonic acid metabolism. Adv Exp Med Biol 469:183–188CrossRefGoogle Scholar
  11. 11.
    Cheng J, Fan XM (2013) Role of cyclooxygenase-2 in gastric cancer development and progression. World J Gastroenterol 19(42):7361–7368.  https://doi.org/10.3748/wjg.v19.i42.7361 CrossRefGoogle Scholar
  12. 12.
    Cheng SE, Lee IT, Lin CC, Wu WL, Hsiao LD, Yang CM (2013) ATP mediates NADPH oxidase/ROS generation and COX-2/PGE2 expression in A549 cells: role of P2 receptor-dependent STAT3 activation. PloS ONE 8(1):e54125.  https://doi.org/10.1371/journal.pone.0054125 CrossRefGoogle Scholar
  13. 13.
    Hugo HJ, Saunders C, Ramsay RG, Thompson EW (2015) New insights on COX-2 in chronic inflammation driving breast cancer growth and metastasis. J Mammary Gland Biol Neoplasia 20(3–4):109–119.  https://doi.org/10.1007/s10911-015-9333-4 CrossRefGoogle Scholar
  14. 14.
    Liu X, Ji Q, Ye N, Sui H, Zhou L, Zhu H, Fan Z, Cai J, Li Q (2015) Berberine inhibits invasion and metastasis of colorectal cancer cells via COX-2/PGE2 mediated JAK2/STAT3 signaling pathway. PloS ONE 10(5):e0123478.  https://doi.org/10.1371/journal.pone.0123478 CrossRefGoogle Scholar
  15. 15.
    Knab LM, Grippo PJ, Bentrem DJ (2014) Involvement of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase. World J Gastroenterol 20(31):10729–10739.  https://doi.org/10.3748/wjg.v20.i31.10729 CrossRefGoogle Scholar
  16. 16.
    Qiu X, Cheng JC, Chang HM, Leung PC (2014) COX2 and PGE2 mediate EGF-induced E-cadherin-independent human ovarian cancer cell invasion. Endocr Relat Cancer 21(4):533–543.  https://doi.org/10.1530/erc-13-0450 CrossRefGoogle Scholar
  17. 17.
    Ruan D, So SP (2014) Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo. Life Sci 116(1):43–50.  https://doi.org/10.1016/j.lfs.2014.07.042 CrossRefGoogle Scholar
  18. 18.
    Wang D, Fu L, Sun H, Guo L, DuBois RN (2015) Prostaglandin E2 promotes colorectal cancer stem cell expansion and metastasis in mice. Gastroenterology 149(7):1884–1895.e1884.  https://doi.org/10.1053/j.gastro.2015.07.064 CrossRefGoogle Scholar
  19. 19.
    Wang J, Zhang L, Kang D, Yang D, Tang Y (2018) Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD-1 in infiltrating CD8(+) T cells in patients with lung cancer. Oncol Lett 15(1):552–558.  https://doi.org/10.3892/ol.2017.7279 Google Scholar
  20. 20.
    Zhang S, Da L, Yang X, Feng D, Yin R, Li M, Zhang Z, Jiang F, Xu L (2014) Celecoxib potentially inhibits metastasis of lung cancer promoted by surgery in mice, via suppression of the PGE2-modulated beta-catenin pathway. Toxicol Lett 225(2):201–207.  https://doi.org/10.1016/j.toxlet.2013.12.014 CrossRefGoogle Scholar
  21. 21.
    Broggini T, Czabanka M, Piffko A, Harms C, Hoffmann C, Mrowka R, Wenke F, Deutsch U, Grotzinger C, Vajkoczy P (2015) ICAM1 depletion reduces spinal metastasis formation in vivo and improves neurological outcome. Eur Spine J 24(10):2173–2181.  https://doi.org/10.1007/s00586-015-3811-7 CrossRefGoogle Scholar
  22. 22.
    Kotteas EA, Boulas P, Gkiozos I, Tsagkouli S, Tsoukalas G, Syrigos KN (2014) The intercellular cell adhesion molecule-1 (icam-1) in lung cancer: implications for disease progression and prognosis. Anticancer Res 34(9):4665–4672Google Scholar
  23. 23.
    Usami Y, Ishida K, Sato S, Kishino M, Kiryu M, Ogawa Y, Okura M, Fukuda Y, Toyosawa S (2013) Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion. Int J Cancer 133(3):568–578.  https://doi.org/10.1002/ijc.28066 CrossRefGoogle Scholar
  24. 24.
    Yu JA, Sadaria MR, Meng X, Mitra S, Ao L, Fullerton DA, Weyant MJ (2012) Lung cancer cell invasion and expression of intercellular adhesion molecule-1 (ICAM-1) are attenuated by secretory phospholipase A(2) inhibition. J Thorac Cardiovasc Surg 143(2):405–411.  https://doi.org/10.1016/j.jtcvs.2011.10.026 CrossRefGoogle Scholar
  25. 25.
    Li CJ, Li YC, Zhang DR, Pan JH (2013) Signal transducers and activators of transcription 3 function in lung cancer. J Cancer Res Ther 9(Suppl 2):S67–S73CrossRefGoogle Scholar
  26. 26.
    Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10(1):48–54.  https://doi.org/10.1038/nm976 CrossRefGoogle Scholar
  27. 27.
    Bennett DT, Reece TB, Foley LS, Sjoberg A, Meng X, Fullerton DA, Weyant MJ (2015) C-terminal tensin-like protein mediates invasion of human lung cancer cells and is regulated by signal transducer and activator of transcription 3. J Thorac Cardiovasc Surg 149(1):369–375.  https://doi.org/10.1016/j.jtcvs.2014.08.087 CrossRefGoogle Scholar
  28. 28.
    Yu JA, Li H, Meng X, Fullerton DA, Nemenoff RA, Mitchell JD, Weyant MJ (2012) Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells. J Thorac Cardiovasc Surg 144(6):1479–1485.  https://doi.org/10.1016/j.jtcvs.2012.08.064 CrossRefGoogle Scholar
  29. 29.
    Mauchley D, Meng X, Johnson T, Fullerton DA, Weyant MJ (2010) Modulation of growth in human esophageal adenocarcinoma cells by group IIa secretory phospholipase A(2). J Thorac Cardiovasc Surg 139(3):591–599.  https://doi.org/10.1016/j.jtcvs.2009.10.061 discussion 599.CrossRefGoogle Scholar
  30. 30.
    Yu JA, Kalatardi S, Dohse J, Sadaria MR, Meng X, Fullerton DA, Weyant MJ (2012) Group IIa sPLA2 inhibition attenuates NF-kappaB activity and promotes apoptosis of lung cancer cells. Anticancer Res 32(9):3601–3607Google Scholar
  31. 31.
    Su CY, Li YS, Han Y, Zhou SJ, Liu ZD (2014) Correlation between expression of cell adhesion molecules CD(4)(4) v6 and E-cadherin and lymphatic metastasis in non- small cell lung cancer. Asian Pac J Cancer Prev 15(5):2221–2224CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Surgery, Division of Cardiothoracic SurgeryUniversity of Colorado School of MedicineAuroraUSA

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