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Open Access 01-12-2016 | Research article

Aspirin inhibits epithelial-to-mesenchymal transition and migration of oncogenic K-ras-expressing non-small cell lung carcinoma cells by down-regulating E-cadherin repressor Slug

Authors: Poulami Khan, Argha Manna, Shilpi Saha, Suchismita Mohanty, Shravanti Mukherjee, Minakshi Mazumdar, Deblina Guha, Tanya Das

Published in: BMC Cancer | Issue 1/2016

Abstract

Background

Cancer metastasis is one of the most common causes of treatment failure and death in cancer patients. It has been acknowledged that aberrant activation of epithelial-to-mesenchymal transition (EMT) program, endows cancer cells with metastatic competence for which E-cadherin switch is a well-established hallmark. Suppression of E-cadherin by its transcriptional repressor Slug is thus a determining factor for EMT. Here, we aimed at discerning (i) the molecular mechanisms that regulate Slug/E-cadherin axis in oncogenic K-ras-expressing non-small cell lung carcinoma (NSCLC) cells, and (ii) the effect of aspirin in modulating the same.

Methods

The migratory behaviour of NSCLC cell line A549 were deciphered by wound healing assay. Further assessment of the molecular mechanisms was done by western blotting, RT-PCR, confocal microscopy, chromatin immunoprecipitation and small interfering RNA (siRNA)-mediated gene silencing.

Results

Here we report that in oncogenic K-ras-expressing A549 cells, Ras/ERK downstream Elk-1 forms p-Elk-1-p300 complex that being directly recruited to SLUG promoter acetylates the same to ensure p65NFκB binding for transcriptional up-regulation of Slug, a transcriptional repressor of E-cadherin. Aspirin inhibits EMT and decelerates the migratory potential of A549 cells by down-regulating Slug and thereby up-regulating E-cadherin. Aspirin impedes activation and nuclear translocation of p65NFκB, essential for this transcription factor being available for SLUG promoter binding. As a consequence, Slug transcription is down-regulated relieving A549 cells from Slug-mediated repression of E-cadherin transcription, thereby diminishing the metastatic potential of these oncogenic Ras-expressing NSCLC cells.

Conclusions

Cumulatively, these results signify a crucial role of the anti-inflammatory agent aspirin as a novel negative regulator of epithelial-to-mesenchymal transition thereby suggesting its candidature as a promising tool for deterring metastasis of highly invasive K-ras-expressing NSCLC cells.

Available only for authorised users

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Wu DW, Lee MC, Hsu NY, Wu TC, Wu JY, Wanget YC, et al. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction. Oncogene. 2015;34(19):2505–15.CrossRefPubMed

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Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994;265(5174):956–9.CrossRefPubMed

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43.

Thun MJ, Jacobs EJ, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol. 2012;9(5):259–67.CrossRefPubMed

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Norrish AE, Jackson RT, McRae CU. Non-steroidal anti-inflammatory drugs and prostate cancer progression. Int J Cancer. 1998;77(4):511–5.CrossRefPubMed

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Gilmore TD, Herscovitch M. Inhibitors of NFκB signaling: 785 and counting. Oncogene. 2006;25(51):6887–99.CrossRefPubMed

46.

Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379(9826):1591–601.CrossRefPubMed

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Wynne S, Djakiew D. NSAID inhibition of prostate cancer cell migration is mediated by Nag-1 induction via the p38 MAPK-p75(NTR) pathway. Mol Cancer Res. 2010;8(12):1656–64.CrossRefPubMedPubMedCentral

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Brady RR, Loveridge CJ, Dunlop MG, Stark LA. c-Src dependency of NSAID-induced effects on NF-kB-mediated apoptosis in colorectal cancer cells. Carcinogenesis. 2011;32(7):1069–77.CrossRefPubMed

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Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.CrossRefPubMedPubMedCentral

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Tsai JH, Yang J. Epithelial–mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013;27(20):2192–206.CrossRefPubMedPubMedCentral

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Lemieux E, Cagnol S, Beaudry K, Carrier J, Rivard N. Oncogenic KRAS signalling promotes the Wnt/β-catenin pathway through LRP6 in colorectal cancer. Oncogene. 2015;34(38):4914–27.CrossRefPubMed

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Shin S, Blenis J. ERK2/Fra1/ZEB pathway induces epithelial-tomesenchymal transition. Cell Cycle. 2010;9(13):2483–4.CrossRefPubMed

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Li QJ, Yang SH, Maeda Y, Sladek FM, Sharrocks AD, Martins-Green M. MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300. EMBO J. 2003;22(2):281–91.CrossRefPubMedPubMedCentral

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Wang Y, Yue B, Yu X, Wang Z, Wang M. SLUG is activated by nuclear factor kappa B and confers human alveolar epithelial A549 cells resistance to tumor necrosis factor-alphainduced apoptosis. World J Surg Oncol. 2013;11:12. doi:10.1186/1477–7819–11–12.CrossRefPubMedPubMedCentral

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Yotsui T, Yasuda O, Kawamoto H, Higuchi M, Chihara Y, Umemoto E, et al. Aspirin prevents adhesion of T lymphoblasts to vascular smooth muscle cells. FEBS Lett. 2007;581(3):427–32.CrossRefPubMed

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Helbig G. Christopherson KW 2nd, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, et al. NFkB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003;278(24):21631–8.CrossRefPubMed

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Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol. 2010;2010:215158.CrossRefPubMedPubMedCentral

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Title: Aspirin inhibits epithelial-to-mesenchymal transition and migration of oncogenic K-ras-expressing non-small cell lung carcinoma cells by down-regulating E-cadherin repressor Slug
Authors: Poulami Khan
Argha Manna
Shilpi Saha
Suchismita Mohanty
Shravanti Mukherjee
Minakshi Mazumdar
Deblina Guha
Tanya Das
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-016-2078-7

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Abstract

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