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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Downregulating CD26/DPPIV by apigenin modulates the interplay between Akt and Snail/Slug signaling to restrain metastasis of lung cancer with multiple EGFR statuses

Authors: Jer-Hwa Chang, Chao-Wen Cheng, Yi-Chieh Yang, Wan-Shen Chen, Wen-Yueh Hung, Jyh-Ming Chow, Pai-Sheng Chen, Michael Hsiao, Wei-Jiunn Lee, Ming-Hsien Chien

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Metastasis rather than the primary cancer determines the survival of cancer patients. Activation of Akt plays a critical role in the epithelial-to-mesenchymal transition (EMT), the initial step in lung cancer metastasis. Apigenin (API), a flavonoid with a potent Akt-inhibitory effect, shows oncostatic activities in various cancers. However, the effects of API on metastasis of non-small cell lung cancer (NSCLC) remain unclear.

Methods

NSCLC cell lines with different epidermal growth factor receptor (EGFR) statuses and in vivo orthotopic bioluminescent xenograft model were employed to determine antitumor activity of API. Western blot and genetic knockdown by shRNA or genetic overexpression by DNA plasmids were performed to explore the underlying mechanisms. The Cancer Genome Atlas (TCGA) database was used to investigate the prognosis of API-targeted genes.

Results

API was demonstrated to inhibit the migration/invasion of NSCLC cells harboring different EGFR statuses via suppressing the Snail/Slug-mediated EMT. Mechanistic investigations showed that CD26/dipeptidyl peptidase IV (DPPIV) was downregulated by API following suppressive interplay of Akt and Snail/Slug signaling to modulate the EMT and the invasive ability of NSCLC cells. CD26 expression was positively correlated with the invasive abilities of NSCLC cells and a worse prognosis of lung cancer patients. Furthermore, we observed that patients with CD26high/Akthigh tumors had the shortest recurrence-free survival times. In vivo, API drastically reduced the growth and metastasis of A549 xenografts through targeting CD26.

Conclusions

CD26 may be a useful biomarker for predicting NSCLC progression. API effectively suppressed lung cancer progression by targeting the CD26-Akt-Snail/Slug signaling pathway.
Appendix
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Literature
1.
2.
3.
Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003;21(16):3016–24.CrossRefPubMed
4.
Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet. 2013;382(9893):709–19.CrossRefPubMed
5.
Wu JY, Shih JY, Chen KY, Yang CH, Yu CJ, Yang PC. Gefitinib therapy in patients with advanced non-small cell lung cancer with or without testing for epidermal growth factor receptor (EGFR) mutations. Medicine. 2011;90(3):159–67.CrossRefPubMed
6.
Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, Halmos B, Pearlberg J, Tsuchihashi Z, Cantley LC, et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst. 2005;97(16):1185–94.CrossRefPubMed
7.
Talbot LJ, Bhattacharya SD, Kuo PC. Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. Int J Biochem Mol Biol. 2012;3(2):117–36.PubMedPubMedCentral
8.
9.
Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, Iwata KK, Gibson N, Haley JD. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 2005;65(20):9455–62.CrossRefPubMed
10.
Akca H, Demiray A, Tokgun O, Yokota J. Invasiveness and anchorage independent growth ability augmented by PTEN inactivation through the PI3K/AKT/NFkB pathway in lung cancer cells. Lung Cancer. 2011;73(3):302–9.CrossRefPubMed
11.
Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS, Chung J. Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J. 2001;15(11):1953–62.CrossRefPubMed
12.
Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, Natesan S, Brugge JS. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol. 2005;171(6):1023–34.CrossRefPubMedPubMedCentral
13.
Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN, Larue L. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 2003;63(9):2172–8.PubMed
14.
Xu W, Yang Z, Lu N. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhes Migr. 2015;9(4):317–24.CrossRef
15.
Liu ZC, Wang HS, Zhang G, Liu H, Chen XH, Zhang F, Chen DY, Cai SH, Du J. AKT/GSK-3beta regulates stability and transcription of snail which is crucial for bFGF-induced epithelial-mesenchymal transition of prostate cancer cells. Biochim Biophys Acta. 2014;1840(10):3096–105.CrossRefPubMed
16.
Hong KO, Kim JH, Hong JS, Yoon HJ, Lee JI, Hong SP, Hong SD. Inhibition of Akt activity induces the mesenchymal-to-epithelial reverting transition with restoring E-cadherin expression in KB and KOSCC-25B oral squamous cell carcinoma cells. J Exp Clin Cancer Res. 2009;28:28.CrossRefPubMedPubMedCentral
17.
Kim JY, Kim YM, Yang CH, Cho SK, Lee JW, Cho M. Functional regulation of Slug/Snail2 is dependent on GSK-3beta-mediated phosphorylation. FEBS J. 2012;279(16):2929–39.CrossRefPubMed
18.
Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH. The role of CD26/dipeptidyl peptidase IV in cancer. Front Biosci. 2008;13:1634–45.CrossRefPubMed
19.
Fox DA, Hussey RE, Fitzgerald KA, Acuto O, Poole C, Palley L, Daley JF, Schlossman SF, Reinherz EL. Ta1, a novel 105 KD human T cell activation antigen defined by a monoclonal antibody. J Immunol. 1984;133(3):1250–6.PubMed
20.
Torimoto Y, Dang NH, Vivier E, Tanaka T, Schlossman SF, Morimoto C. Coassociation of CD26 (dipeptidyl peptidase IV) with CD45 on the surface of human T lymphocytes. J Immunol. 1991;147(8):2514–7.PubMed
21.
Stremenova J, Krepela E, Mares V, Trim J, Dbaly V, Marek J, Vanickova Z, Lisa V, Yea C, Sedo A. Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade. Int J Oncol. 2007;31(4):785–92.PubMed
22.
Bauvois B, De Meester I, Dumont J, Rouillard D, Zhao HX, Bosmans E. Constitutive expression of CD26/dipeptidylpeptidase IV on peripheral blood B lymphocytes of patients with B chronic lymphocytic leukaemia. Br J Cancer. 1999;79(7–8):1042–8.CrossRefPubMedPubMedCentral
23.
Liang PI, Yeh BW, Li WM, Chan TC, Chang IW, Huang CN, Li CC, Ke HL, Yeh HC, Wu WJ, et al. DPP4/CD26 overexpression in urothelial carcinoma confers an independent prognostic impact and correlates with intrinsic biological aggressiveness. Oncotarget. 2017;8(2):2995–3008.CrossRefPubMed
24.
Pang R, Law WL, Chu AC, Poon JT, Lam CS, Chow AK, Ng L, Cheung LW, Lan XR, Lan HY, et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6(6):603–15.CrossRefPubMed
25.
Yamaguchi U, Nakayama R, Honda K, Ichikawa H, Hasegawa T, Shitashige M, Ono M, Shoji A, Sakuma T, Kuwabara H, et al. Distinct gene expression-defined classes of gastrointestinal stromal tumor. J Clin Oncol. 2008;26(25):4100–8.CrossRefPubMed
26.
Jang JH, Baerts L, Waumans Y, De Meester I, Yamada Y, Limani P, Gil-Bazo I, Weder W, Jungraithmayr W. Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice. Clin Exp Metastasis. 2015;32(7):677–87.CrossRefPubMed
27.
28.
29.
30.
Zhou Z, Tang M, Liu Y, Zhang Z, Lu R, Lu J. Apigenin inhibits cell proliferation, migration, and invasion by targeting Akt in the A549 human lung cancer cell line. Anti-Cancer Drugs. 2017;28(4):446–56.CrossRefPubMed
31.
Chu YW, Yang PC, Yang SC, Shyu YC, Hendrix MJ, Wu R, Wu CW. Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol. 1997;17(3):353–60.CrossRefPubMed
32.
Lee YC, Saijo N, Sasaki Y, Takahashi H, Sakurai M, Ishihara J, Hoshi A, Chen KM, Hamburger AW. Clonogenic patterns of human pulmonary adenocarcinoma cell lines (PC-9, PC-13 and PC-14) and how they influence the results of test for chemosensitivity to cisplatin in the human tumor clonogenic assay. Jpn J Clin Oncol. 1985;15(4):637–44.PubMed
33.
Yang SF, Lee WJ, Tan P, Tang CH, Hsiao M, Hsieh FK, Chien MH. Upregulation of miR-328 and inhibition of CREB-DNA-binding activity are critical for resveratrol-mediated suppression of matrix metalloproteinase-2 and subsequent metastatic ability in human osteosarcomas. Oncotarget. 2015;6(5):2736–53.PubMed
34.
Lee WJ, Hsiao M, Chang JL, Yang SF, Tseng TH, Cheng CW, Chow JM, Lin KH, Lin YW, Liu CC, et al. Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft. Arch Toxicol. 2015;89(7):1103–17.CrossRefPubMed
35.
Chien MH, Lee WJ, Hsieh FK, Li CF, Cheng TY, Wang MY, Chen JS, Chow JM, Jan YH, Hsiao M, et al. Keap1-Nrf2 interaction suppresses cell motility in lung adenocarcinomas by targeting the S100P protein. Clin Cancer Res. 2015;21(20):4719–32.CrossRefPubMed
36.
Mahmood MQ, Ward C, Muller HK, Sohal SS, Walters EH. Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease. Med Oncol. 2017;34(3):45.CrossRefPubMed
37.
Ming SH, Sun TY, Xiao W, Xu XM. Matrix metalloproteinases-2, −9 and tissue inhibitor of metallo-proteinase-1 in lung cancer invasion and metastasis. Chin Med J. 2005;118(1):69–72.PubMed
38.
39.
Liu CW, Li CH, Peng YJ, Cheng YW, Chen HW, Liao PL, Kang JJ, Yeng MH. Snail regulates Nanog status during the epithelial-mesenchymal transition via the Smad1/Akt/GSK3beta signaling pathway in non-small-cell lung cancer. Oncotarget. 2014;5(11):3880–94.PubMedPubMedCentral
40.
Li P, Lin X, Zhang JR, Li Y, Lu J, Huang FC, Zheng CH, Xie JW, Wang JB, Huang CM. The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer. Oncotarget. 2016;7(9):10650–62.PubMedPubMedCentral
41.
Stallings-Mann ML, Waldmann J, Zhang Y, Miller E, Gauthier ML, Visscher DW, Downey GP, Radisky ES, Fields AP, Radisky DC. Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression. Sci Transl Med. 2012;4(142):142ra195.CrossRef
42.
Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis. 2011;32(9):1299–304.CrossRefPubMed
43.
Hakomori S. Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv Cancer Res. 1989;52:257–331.CrossRefPubMed
44.
Lam CS, Cheung AH, Wong SK, Wan TM, Ng L, Chow AK, Cheng NS, Pak RC, Li HS, Man JH, et al. Prognostic significance of CD26 in patients with colorectal cancer. PLoS One. 2014;9(5):e98582.CrossRefPubMedPubMedCentral
45.
Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH. CD26 expression on T cell lines increases SDF-1-alpha-mediated invasion. Br J Cancer. 2009;101(6):983–91.CrossRefPubMedPubMedCentral
46.
Inamoto T, Yamochi T, Ohnuma K, Iwata S, Kina S, Inamoto S, Tachibana M, Katsuoka Y, Dang NH, Morimoto C. Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27(kip1) enhancement, and disruption of binding to the extracellular matrix. Clin Cancer Res. 2006;12(11 Pt 1):3470–7.CrossRefPubMed
47.
Fan J, Johnson MH, Lila MA, Yousef G, de Mejia EG. Berry and Citrus phenolic compounds inhibit dipeptidyl peptidase IV: implications in diabetes management. Evid Based Complement Alternat Med. 2013;2013:479505.PubMedPubMedCentral
48.
Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, Dargemont C, de Herreros AG, Bellacosa A, Larue L. Activation of NF-kappaB by Akt upregulates snail expression and induces epithelium mesenchyme transition. Oncogene. 2007;26(53):7445–56.CrossRefPubMed
49.
Jacobsen K, Bertran-Alamillo J, Molina MA, Teixido C, Karachaliou N, Pedersen MH, Castellvi J, Garzon M, Codony-Servat C, Codony-Servat J, et al. Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer. Nat Commun. 2017;8(1):410.CrossRefPubMedPubMedCentral
50.
Nukaga S, Yasuda H, Tsuchihara K, Hamamoto J, Masuzawa K, Kawada I, Naoki K, Matsumoto S, Mimaki S, Ikemura S, et al. Amplification of EGFR wild-type alleles in non-small cell lung Cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. Cancer Res. 2017;77(8):2078–89.CrossRefPubMed
51.
Li L, Qi L, Liang Z, Song W, Liu Y, Wang Y, Sun B, Zhang B, Cao W. Transforming growth factor-beta1 induces EMT by the transactivation of epidermal growth factor signaling through HA/CD44 in lung and breast cancer cells. Int J Mol Med. 2015;36(1):113–22.CrossRefPubMedPubMedCentral
52.
Henderson V, Smith B, Burton LJ, Randle D, Morris M, Odero-Marah VA. Snail promotes cell migration through PI3K/AKT-dependent Rac1 activation as well as PI3K/AKT-independent pathways during prostate cancer progression. Cell Adhes Migr. 2015;9(4):255–64.CrossRef
53.
Escriva M, Peiro S, Herranz N, Villagrasa P, Dave N, Montserrat-Sentis B, Murray SA, Franci C, Gridley T, Virtanen I, et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol Cell Biol. 2008;28(5):1528–40.CrossRefPubMedPubMedCentral
54.
Uygur B, Abramo K, Leikina E, Vary C, Liaw L, Wu WS. SLUG is a direct transcriptional repressor of PTEN tumor suppressor. Prostate. 2015;75(9):907–16.CrossRefPubMedPubMedCentral
55.
56.
Perez-Ramirez C, Canadas-Garre M, Molina MA, Faus-Dader MJ, Calleja-Hernandez MA. PTEN and PI3K/AKT in non-small-cell lung cancer. Pharmacogenomics. 2015;16(16):1843–62.CrossRefPubMed
57.
58.
Chang JH, Lai SL, Chen WS, Hung WY, Chow JM, Hsiao M, Lee WJ, Chien MH. Quercetin suppresses the metastatic ability of lung cancer through inhibiting snail-dependent Akt activation and snail-independent ADAM9 expression pathways. Biochim Biophys Acta. 2017;1864(10):1746–58.CrossRefPubMed
Metadata
Title
Downregulating CD26/DPPIV by apigenin modulates the interplay between Akt and Snail/Slug signaling to restrain metastasis of lung cancer with multiple EGFR statuses
Authors
Jer-Hwa Chang
Chao-Wen Cheng
Yi-Chieh Yang
Wan-Shen Chen
Wen-Yueh Hung
Jyh-Ming Chow
Pai-Sheng Chen
Michael Hsiao
Wei-Jiunn Lee
Ming-Hsien Chien
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0869-1

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