Zileuton Suppresses Cholangiocarcinoma Cell Proliferation and Migration Through Inhibition of the Akt Signaling Pathway

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2018 Nov 10

PMID 30410359

Citations 14

Authors

Sasikamon Khophai

Malinee Thanee

Anchalee Techasen

Nisana Namwat

Poramate Klanrit

Attapol Titapun

Apiwat Jarearnrat

Prakasit Sa-Ngiamwibool

Watcharin Loilome

Affiliations

Soon will be listed here.

Abstract

Background: Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15-lipoxygenase (15-LOX-1) converts LTs into lipoxins (LXs), pro-resolving lipid mediators. LXs are involved in the attenuation of inflammation and cancer development.

Purpose: We aimed to investigate the lipid mediator pathways, especially the LTs and LXs pathways, by studying 5-LOX and 15-LOX-1 expression in human cholangiocarcinoma (CCA) tissue. We also investigated the efficiency of zileuton (5-LOX inhibitor) treatment and BML-111 (LXA4 analog) addition on CCA cell lines properties.

Patients And Methods: The expression of 5-LOX and 15-LOX-1 in fifty human cholangiocarcinoma (CCA) tissue was analyzed using immunohistochemical staining. In addition, the effect of zileuton and BML-111 on CCA cell growth and migration was demonstrated using a cell viability assay and wound-healing assay, respectively. Furthermore, the molecular mechanism by which zileuton inhibits CCA cell migration was revealed using immunofluorescent staining and western blot analysis, respectively.

Results: We demonstrate that the upregulation of 5-LOX is significantly correlated with CCA recurrent status. A positive 15-LOX-1 signal was significantly associated with a longer survival time in CCA patients. We found that co-expression of 5-LOX and 15-LOX-1 resulted in a relatively good prognosis in CCA patients. In addition, zileuton could inhibit CCA cell migration as well as BML-111. Interestingly, zileuton treatment not only downregulated 5-LOX, but also upregulated 15-LOX-1, together with reversing the epithelial-mesenchymal transition to mesenchymal-epithelial transition phenotype as observed in EMT marker western blot.

Conclusion: These findings suggest that 5-LOX and 15-LOX-1 play a key role in CCA and may serve as targets for CCA therapy.

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References

Zhou G, Ding X, Wu S, Zhang H, Cao W, Qu L . Inhibition of 5-lipoxygenase triggers apoptosis in pancreatic cancer cells. Oncol Rep. 2014; 33(2):661-8. DOI: 10.3892/or.2014.3650. View

Mezhybovska M, Wikstrom K, Ohd J, Sjolander A . The inflammatory mediator leukotriene D4 induces beta-catenin signaling and its association with antiapoptotic Bcl-2 in intestinal epithelial cells. J Biol Chem. 2006; 281(10):6776-84. DOI: 10.1074/jbc.M509999200. View

Peters-Golden M, Henderson Jr W . Leukotrienes. N Engl J Med. 2007; 357(18):1841-54. DOI: 10.1056/NEJMra071371. View

Hagmann W . Cell proliferation status, cytokine action and protein tyrosine phosphorylation modulate leukotriene biosynthesis in a basophil leukaemia and a mastocytoma cell line. Biochem J. 1994; 299 ( Pt 2):467-72. PMC: 1138295. DOI: 10.1042/bj2990467. View

Kupczyk M, Kuna P . [The role of leukotrienes in inflammation and leukotriene inhibitors]. Pol Merkur Lekarski. 1999; 7(39):85-93. View

Ivaska J, Pallari H, Nevo J, Eriksson J . Novel functions of vimentin in cell adhesion, migration, and signaling. Exp Cell Res. 2007; 313(10):2050-62. DOI: 10.1016/j.yexcr.2007.03.040. View

Busse . Leukotrienes and inflammation . Am J Respir Crit Care Med. 1998; 157(6 Pt 1):S210-3. View

Sripa B, Pairojkul C . Cholangiocarcinoma: lessons from Thailand. Curr Opin Gastroenterol. 2008; 24(3):349-56. PMC: 4130346. DOI: 10.1097/MOG.0b013e3282fbf9b3. View

Sarveswaran S, Thamilselvan V, Brodie C, Ghosh J . Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon. Biochim Biophys Acta. 2011; 1813(12):2108-17. PMC: 3541030. DOI: 10.1016/j.bbamcr.2011.07.015. View

10.

Heslin M, Hawkins A, Boedefeld W, Arnoletti J, Frolov A, Soong R . Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer. Ann Surg. 2005; 241(6):941-6. PMC: 1357173. DOI: 10.1097/01.sla.0000164177.95620.c1. View

11.

Xu X, Deng J, Yuan G, Yang F, Guo H, Xiang M . 5-Lipoxygenase contributes to the progression of hepatocellular carcinoma. Mol Med Rep. 2011; 4(6):1195-200. DOI: 10.3892/mmr.2011.547. View

12.

Melstrom L, Bentrem D, Salabat M, Kennedy T, Ding X, Strouch M . Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model. Clin Cancer Res. 2008; 14(20):6525-30. DOI: 10.1158/1078-0432.CCR-07-4631. View

13.

Maruyama M, Kobayashi N, Westerman K, Sakaguchi M, Allain J, Totsugawa T . Establishment of a highly differentiated immortalized human cholangiocyte cell line with SV40T and hTERT. Transplantation. 2004; 77(3):446-51. DOI: 10.1097/01.TP.0000110292.73873.25. View

14.

Roos J, Oancea C, Heinssmann M, Khan D, Held H, Kahnt A . 5-Lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia. Cancer Res. 2014; 74(18):5244-55. DOI: 10.1158/0008-5472.CAN-13-3012. View

15.

Huang L, Wu R, Xu A . Epithelial-mesenchymal transition in gastric cancer. Am J Transl Res. 2016; 7(11):2141-58. PMC: 4697696. View

16.

Serhan C, Krishnamoorthy S, Recchiuti A, Chiang N . Novel anti-inflammatory--pro-resolving mediators and their receptors. Curr Top Med Chem. 2011; 11(6):629-47. PMC: 3094721. DOI: 10.2174/1568026611109060629. View

17.

Powell W, Rokach J . Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE. Prog Lipid Res. 2005; 44(2-3):154-83. DOI: 10.1016/j.plipres.2005.04.002. View

18.

Massoumi R, Sjolander A . The role of leukotriene receptor signaling in inflammation and cancer. ScientificWorldJournal. 2007; 7:1413-21. PMC: 5900856. DOI: 10.1100/tsw.2007.200. View

19.

Wasilewicz M, Kolodziej B, Bojulko T, Kaczmarczyk M, Sulzyc-Bielicka V, Bielicki D . Overexpression of 5-lipoxygenase in sporadic colonic adenomas and a possible new aspect of colon carcinogenesis. Int J Colorectal Dis. 2010; 25(9):1079-85. PMC: 2912725. DOI: 10.1007/s00384-010-0980-z. View

20.

Xu F, Zhou X, Hao J, Dai H, Zhang J, He Y . Lipoxin A and its analog suppress hepatocarcinoma cell epithelial-mesenchymal transition, migration and metastasis via regulating integrin-linked kinase axis. Prostaglandins Other Lipid Mediat. 2018; 137:9-19. DOI: 10.1016/j.prostaglandins.2018.05.007. View