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27.11.2021 | Original Article

Metformin inhibits human non-small cell lung cancer by regulating AMPK–CEBPB–PDL1 signaling pathway

verfasst von: Tao Lu, Ming Li, Mengnan Zhao, Yiwei Huang, Guoshu Bi, Jiaqi Liang, Zhencong Chen, Yuansheng Zheng, Junjie Xi, Zongwu Lin, Cheng Zhan, Wei Jiang, Qun Wang, Lijie Tan

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2022

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Abstract

Metformin has been found to have inhibitory effects on a variety of tumors. However, its effects on non-small cell lung cancer (NSCLC) remain unclear. We demonstrated that metformin could inhibit the proliferation of A549 and H1299 cells. RNA transcriptome sequencing revealed that PDL1 was significantly downregulated in both cell types following treatment with metformin (P < 0.001). Jaspar analysis and chromatin immunoprecipitation showed that CEBPB could directly bind the promoter region of PDL1. Western blotting showed that protein expression of the isoforms CEBPB-LAP*, CEBPB-LAP, and CEBPB-LIP was significantly upregulated and the LIP/LAP ratio was increased. Gene chip analysis showed that PDL1 was significantly upregulated in A549-CEBPB-LAP cells and significantly downregulated in A549-CEBPB-LIP cells (P < 0.05) compared with CEBPB-NC cells. Dual-luciferase reporter gene assay showed that CEBPB-LAP overexpression could promote transcription of PDL1 and CEBPB-LIP overexpression could inhibit the process. Functional assays showed that the changes in CEBPB isoforms affected the function of NSCLC cells. Western blotting showed that metformin could regulate the function of NSCLC cells via AMPK–CEBPB–PDL1 signaling. Animal experiments showed that tumor growth was significantly inhibited by metformin, and atezolizumab and metformin had a synergistic effect on tumor growth. A total of 1247 patients were retrospectively analyzed, including 166 and 1081 patients in metformin and control groups, respectively. The positive rate of PDL1 was lower than that of the control group (HR = 0.338, 95% CI = 0.235–0.487; P < 0.001). In conclusion, metformin inhibited the proliferation of NSCLC cells and played an anti-tumor role in an AMPK–CEBPB–PDL1 signaling-dependent manner.

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Yang P, Allen MS, Aubry MC et al (2005) Clinical features of 5,628 primary lung cancer patients: experience at mayo clinic from 1997 to 2003. Chest 128:452–462. https://doi.org/10.1378/chest.128.1.452CrossRefPubMed

Wistuba II, Gelovani JG, Jacoby JJ, Davis SE, Herbst RS (2011) Methodological and practical challenges for personalized cancer therapies. Nat Rev Clin Oncol 8:135–141. https://doi.org/10.1038/nrclinonc.2011.2CrossRefPubMed

Li JX, Huang JM, Jiang ZB, Li RZ, Sun A, Lai-Han Leung E, Yan PY (2019) Current clinical progress of PD-1/PD-L1 immunotherapy and potential combination treatment in non-small cell lung cancer. Integr Cancer Ther 18:1534735419890020. https://doi.org/10.1177/1534735419890020CrossRefPubMedPubMedCentral

Clark CA, Gupta HB, Sareddy G et al (2016) Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis, and autophagy in ovarian cancer and melanoma. Cancer Res 76:6964–6974. https://doi.org/10.1158/0008-5472.CAN-16-0258CrossRefPubMedPubMedCentral

Zhang JJ, Zhang QS, Li ZQ, Zhou JW, Du J (2019) Metformin attenuates PD-L1 expression through activating hippo signaling pathway in colorectal cancer cells. Am J Trans Res 11:6965–6976

Xiong W, Hsieh CC, Kurtz AJ, Rabek JP, Papaconstantinou J (2001) Regulation of CCAAT/enhancer-binding protein-beta isoform synthesis by alternative translational initiation at multiple AUG start sites. Nucl Acids Res 29:3087–3098. https://doi.org/10.1093/nar/29.14.3087CrossRefPubMedPubMedCentral

Won C, Kim BH, Yi EH et al (2015) Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. Hepatology 62:1160–1173. https://doi.org/10.1002/hep.27968CrossRefPubMed

Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T (1990) A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J 9:1897–1906CrossRef

Burgess-Beusse BL, Timchenko NA, Darlington GJ (1999) CCAAT/enhancer binding protein alpha (C/EBPalpha) is an important mediator of mouse C/EBPbeta protein isoform production. Hepatology 29:597–601. https://doi.org/10.1002/hep.510290245CrossRefPubMed

10.

Descombes P, Chojkier M, Lichtsteiner S, Falvey E, Schibler U (1990) LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes Dev 4:1541–1551. https://doi.org/10.1101/gad.4.9.1541CrossRefPubMed

11.

Maehara O, Ohnishi S, Asano A, Suda G, Natsuizaka M, Nakagawa K, Kobayashi M, Sakamoto N, Takeda H (2019) Metformin regulates the expression of CD133 Through the AMPK-CEBPbeta pathway in hepatocellular carcinoma cell lines. Neoplasia 21:545–556. https://doi.org/10.1016/j.neo.2019.03.007CrossRefPubMedPubMedCentral

12.

Vallianou NG, Evangelopoulos A, Kazazis C (2013) Metformin and cancer. Rev Diabet Stud: RDS 10:228–235. https://doi.org/10.1900/RDS.2013.10.228CrossRefPubMed

13.

Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, Chen HH, Su WC (2013) Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol 49:241–250. https://doi.org/10.1165/rcmb.2012-0244OCCrossRefPubMed

14.

Queiroz EA, Puukila S, Eichler R et al (2014) Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PLoS ONE 9:e98207. https://doi.org/10.1371/journal.pone.0098207CrossRefPubMedPubMedCentral

15.

Vernieri C, Signorelli D, Galli G et al (2019) Exploiting fasting-mimicking diet and metformin to improve the efficacy of platinum-pemetrexed chemotherapy in advanced LKB1-inactivated lung adenocarcinoma: the FAME trial. Clin Lung Cancer 20:e413–e417. https://doi.org/10.1016/j.cllc.2018.12.011CrossRefPubMed

16.

Shackelford DB, Abt E, Gerken L et al (2013) LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23:143–158. https://doi.org/10.1016/j.ccr.2012.12.008CrossRefPubMedPubMedCentral

17.

Graham GG, Punt J, Arora M et al (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50:81–98. https://doi.org/10.2165/11534750-000000000-00000CrossRefPubMed

18.

Gravel SP, Hulea L, Toban N et al (2014) Serine deprivation enhances antineoplastic activity of biguanides. Cancer Res 74:7521–7533. https://doi.org/10.1158/0008-5472.CAN-14-2643-TCrossRefPubMed

19.

Chandel NS, Avizonis D, Reczek CR et al (2016) Are metformin doses used in murine cancer models clinically relevant? Cell Metab 23:569–570. https://doi.org/10.1016/j.cmet.2016.03.010CrossRefPubMed

20.

Zhou H, Liu J, Zhang Y, Zhang L (2019) Inflammatory bowel disease associated with the combination treatment of nivolumab and metformin: data from the FDA adverse event reporting system. Cancer Chemother Pharmacol 83:599–601. https://doi.org/10.1007/s00280-018-03763-5CrossRefPubMed

21.

Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. https://doi.org/10.1038/nrc3239CrossRefPubMedPubMedCentral

22.

Kleffel S, Posch C, Barthel SR et al (2015) Melanoma cell-Intrinsic PD-1 receptor functions promote tumor growth. Cell 162:1242–1256. https://doi.org/10.1016/j.cell.2015.08.052CrossRefPubMedPubMedCentral

23.

Chang CH, Qiu J, O’Sullivan D et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241. https://doi.org/10.1016/j.cell.2015.08.016CrossRefPubMedPubMedCentral

24.

Zheng A, Li F, Chen F, Zuo J, Wang L, Wang Y, Chen S, Xiao B, Tao Z (2019) PDL1 promotes head and neck squamous cell carcinoma cell growth through mTOR signaling. Oncol Rep 41:2833–2843. https://doi.org/10.3892/or.2019.7053CrossRefPubMedPubMedCentral

25.

Cao Y, Zhang L, Kamimura Y, Ritprajak P, Hashiguchi M, Hirose S, Azuma M (2011) B7–H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. Cancer Res 71:1235–1243. https://doi.org/10.1158/0008-5472.CAN-10-2217CrossRefPubMed

26.

Alsuliman A, Colak D, Al-Harazi O, Fitwi H, Tulbah A, Al-Tweigeri T, Al-Alwan M, Ghebeh H (2015) Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol Cancer 14:149. https://doi.org/10.1186/s12943-015-0421-2CrossRefPubMedPubMedCentral

27.

Ghebeh H, Tulbah A, Mohammed S, Elkum N, Bin Amer SM, Al-Tweigeri T, Dermime S (2007) Expression of B7–H1 in breast cancer patients is strongly associated with high proliferative Ki-67-expressing tumor cells. Int J Cancer 121:751–758. https://doi.org/10.1002/ijc.22703CrossRefPubMed

28.

Qorraj M, Bruns H, Bottcher M, Weigand L, Saul D, Mackensen A, Jitschin R, Mougiakakos D (2017) The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia. Leukemia 31:470–478. https://doi.org/10.1038/leu.2016.214CrossRefPubMed

29.

Mariathasan S, Turley SJ, Nickles D et al (2018) TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544–548. https://doi.org/10.1038/nature25501CrossRefPubMedPubMedCentral

30.

Russell A, Boone B, Jiang A, Sealy L (2010) Genomic profiling of C/EBPbeta2 transformed mammary epithelial cells: a role for nuclear interleukin-1beta. Cancer Biol Ther 10:509–519. https://doi.org/10.4161/cbt.10.5.12725CrossRefPubMedPubMedCentral

31.

Regalo G, Forster S, Resende C et al (2016) C/EBPbeta regulates homeostatic and oncogenic gastric cell proliferation. J Mol Med 94:1385–1395. https://doi.org/10.1007/s00109-016-1447-7CrossRefPubMed

32.

Sundfeldt K, Ivarsson K, Carlsson M, Enerback S, Janson PO, Brannstrom M, Hedin L (1999) The expression of CCAAT/enhancer binding protein (C/EBP) in the human ovary in vivo: specific increase in C/EBPbeta during epithelial tumour progression. Br J Cancer 79:1240–1248. https://doi.org/10.1038/sj.bjc.6690199CrossRefPubMedPubMedCentral

33.

Rask K, Thorn M, Ponten F, Kraaz W, Sundfeldt K, Hedin L, Enerback S (2000) Increased expression of the transcription factors CCAAT-enhancer binding protein-beta (C/EBBeta) and C/EBzeta (CHOP) correlate with invasiveness of human colorectal cancer. Int J Cancer 86:337–343. https://doi.org/10.1002/(sici)1097-0215(20000501)86:3%3c337::aid-ijc6%3e3.0.co;2-3CrossRefPubMed

34.

Li Y, Bevilacqua E, Chiribau CB, Majumder M, Wang C, Croniger CM, Snider MD, Johnson PF, Hatzoglou M (2008) Differential control of the CCAAT/enhancer-binding protein beta (C/EBPbeta) products liver-enriched transcriptional activating protein (LAP) and liver-enriched transcriptional inhibitory protein (LIP) and the regulation of gene expression during the response to endoplasmic reticulum stress. J Biol Chem 283:22443–22456. https://doi.org/10.1074/jbc.M801046200CrossRefPubMedPubMedCentral

35.

Wethmar K, Begay V, Smink JJ, Zaragoza K, Wiesenthal V, Dorken B, Calkhoven CF, Leutz A (2010) C/EBPbetaDeltauORF mice–a genetic model for uORF-mediated translational control in mammals. Genes Dev 24:15–20. https://doi.org/10.1101/gad.557910CrossRefPubMedPubMedCentral

36.

Smink JJ, Begay V, Schoenmaker T, Sterneck E, de Vries TJ, Leutz A (2009) Transcription factor C/EBPbeta isoform ratio regulates osteoclastogenesis through MafB. EMBO J 28:1769–1781. https://doi.org/10.1038/emboj.2009.127CrossRefPubMedPubMedCentral

37.

Buck M, Poli V, Hunter T, Chojkier M (2001) C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Mol Cell 8:807–816. https://doi.org/10.1016/s1097-2765(01)00374-4CrossRefPubMed

38.

Tang QQ, Gronborg M, Huang H, Kim JW, Otto TC, Pandey A, Lane MD (2005) Sequential phosphorylation of CCAAT enhancer-binding protein beta by MAPK and glycogen synthase kinase 3beta is required for adipogenesis. Proc Natl Acad Sci USA 102:9766–9771. https://doi.org/10.1073/pnas.0503891102CrossRefPubMedPubMedCentral

39.

Li X, Kim JW, Gronborg M, Urlaub H, Lane MD, Tang QQ (2007) Role of cdk2 in the sequential phosphorylation/activation of C/EBPbeta during adipocyte differentiation. Proc Natl Acad Sci USA 104:11597–11602. https://doi.org/10.1073/pnas.0703771104CrossRefPubMedPubMedCentral

Titel: Metformin inhibits human non-small cell lung cancer by regulating AMPK–CEBPB–PDL1 signaling pathway
verfasst von: Tao Lu
Ming Li
Mengnan Zhao
Yiwei Huang
Guoshu Bi
Jiaqi Liang
Zhencong Chen
Yuansheng Zheng
Junjie Xi
Zongwu Lin
Cheng Zhan
Wei Jiang
Qun Wang
Lijie Tan
Publikationsdatum: 27.11.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 7/2022
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-021-03116-x

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Metformin inhibits human non-small cell lung cancer by regulating AMPK–CEBPB–PDL1 signaling pathway

Abstract

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Abstract

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