3 Biotech

, 9:384 | Cite as

2-Amino-4-(1-piperidine) pyridine exhibits inhibitory effect on colon cancer through suppression of FOXA2 expression

  • Jieshu Wang
  • Bo Li
  • Kun Zhao
  • Xinyou SuEmail author
Original Article


The present study was aimed to investigate the effect of 2-amino-4-(1-piperidine) pyridine on migration and invasion of colon cancer cells. Treatment of colon cancer cells with 2-amino-4-(1-piperidine) pyridine reduced viability in concentration-based manner. The migration potential of HCT116 and HT29 cells was also suppressed on treatment with 2-amino-4-(1-piperidine) pyridine. In HCT116 and HT29 cells, apoptotic cell proportion was increased significantly by 2-amino-4-(1-piperidine) pyridine treatment. The expression of EMT and Vimentin in HCT116 and HT29 cells was reduced markedly on treatment with 2-amino-4-(1-piperidine) pyridine. The expression of E-cadherin was increased in HCT116 and HT29 cells by 2-amino-4-(1-piperidine) pyridine treatment. Treatment with 2-amino-4-(1-piperidine) pyridine reduced the expression of FOXA2 in HCT116 and HT29 cells. The 2-amino-4-(1-piperidine) pyridine treatment reduced growth of tumor in vivo in mice model. In summary, 2-amino-4-(1-piperidine) pyridine treatment inhibits colon cancer cell proliferation through down-regulation of FOXA2 expression. Therefore, 2-amino-4-(1-piperidine) pyridine can be used for the treatment of colon cancer.


Mesenchymal transition Malignant Forkhead box Metastasis 


Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. Ancey PB, Ecsedi S, Lambert MP, Talukdar FR, Cros MP, Glaise D, Narvaez DM, Chauvet V, Herceg Z, Corlu A, Hernandez-Vargas H (2017) TET-catalyzed 5-hydroxymethylation precedes HNF4A promoter choice during differentiation of bipotent liver progenitors. Stem Cell Rep 9:264–278Google Scholar
  2. Aquino RGF, Vasques PHD, Cavalcante DIM, Oliveira ALS, Oliveira BMK, Pinheiro LGP (2017) Invasive ductal carcinoma: relationship between pathological characteristics and the presence of axillary metastasis in 220 cases. Rev Col Bras Cir 44:163–170PubMedGoogle Scholar
  3. Bastidas-Ponce A, Roscioni SS, Burtscher I, Bader E, Sterr M, Bakhti M, Lickert H (2017) Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells. Mol Metab 6:524–534PubMedPubMedCentralGoogle Scholar
  4. Berg DT, Gerlitz B, Sharma GR, Richardson MA, Stephens EJ, Grubbs RL, Holmes KC, Fynboe K, Montani D, Cramer MS et al (2006) FoxA2 involvement in suppression of protein C, an outcome predictor in experimental sepsis. Clin Vaccine Immunol 13:426–432PubMedPubMedCentralGoogle Scholar
  5. Birchmeier W, Behrens J (1994) Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198:11–26PubMedGoogle Scholar
  6. Cao Z, Zheng X, Cao L, Liang N (2017) MicroRNA-539 inhibits the epithelial-mesenchymal transition of esophageal cancer cells by twist-related protein 1-mediated modulation of melanoma associated antigen A4 (MAGEA4). Oncol Res 2017:385Google Scholar
  7. Chen Y, Fang L, Li G, Zhang J, Li C, Ma M, Guan C, Bai F, Lyu J, Meng QH (2017) Synergistic inhibition of colon cancer growth by the combination of methylglyoxal and silencing of glyoxalase I mediated by the STAT1 pathway. Oncotarget 8:54838–54857PubMedPubMedCentralGoogle Scholar
  8. Chino XMS, Martinez CJ, Garzón VRV, González IÁ, Treviño SV, Bujaidar EM, Ortiz GD, Hoyos RB (2017) Cooked chickpea consumption inhibits colon carcinogenesis in mice induced with azoxymethane and dextran sulfate sodium. J Am Coll Nutr 36:391–398PubMedGoogle Scholar
  9. Cho N, Ransom TT, Sigmund J, Tran T, Cichewicz RH, Goetz M, Beutler JA (2017) Growth inhibition of colon cancer and melanoma cells by versiol derivatives from a paraconiothyrium species. J Nat Prod 80:2037–2044PubMedPubMedCentralGoogle Scholar
  10. Christofori G, Semb H (1999) The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 24:73–76PubMedGoogle Scholar
  11. Cusimano A, Balasus D, Azzolina A, Augello G, Emma MR, Di Sano C, Gramignoli R, Strom SC, McCubrey JA, Montalto G, Cervello M (2017) Oleocanthal exerts antitumor effects on human liver and colon cancer cells through ROS generation. Int J Oncol 51:533–544PubMedGoogle Scholar
  12. Goel G, Sun W (2015) Advances in the management of gastrointestinal cancers—an upcoming role of immune checkpoint blockade. J Hematol Oncol 8:86PubMedPubMedCentralGoogle Scholar
  13. Hou PC, Li YH, Lin SC, Lin SC, Lee JC, Lin BW, Liou JP, Chang JY, Kuo CC, Liu YM et al (2017) Hypoxia-induced downregulation of DUSP-2 phosphatase drives colon cancer stemness. Cancer Res 77:4305–4316PubMedGoogle Scholar
  14. Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Invest 119:1420–1428PubMedPubMedCentralGoogle Scholar
  15. Kanaki M, Tiniakou I, Thymiakou E, Kardassis D (2017) Physical and functional interactions between nuclear receptor LXRα and the forkhead box transcription factor FOXA2 regulate the response of the human lipoprotein lipase gene to oxysterols in hepatic cells. Biochim Biophys Acta 1860:848–860Google Scholar
  16. Kondratyeva LG, Sveshnikova AA, Grankina EV, Chernov IP, Kopantseva MR, Kopantzev EP, Sverdlov ED (2016) Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGFβ1 epithelial–mesenchymal transition. Dokl Biochem Biophys 469:257–259PubMedGoogle Scholar
  17. Laudato S, Patil N, Abba ML, Leupold JH, Benner A, Gaiser T, Marx A, Allgayer H (2017) P53-induced miR-30e-5p inhibits colorectal cancer invasion and metastasis by targeting ITGA6 and ITGB1. Int J Cancer 141:1879–1890PubMedGoogle Scholar
  18. Lazarova D, Bordonaro M (2017) ZEB1 mediates drug resistance and EMT in p300-deficient CRC. J Cancer 8:1453–1459PubMedPubMedCentralGoogle Scholar
  19. Li J, Dantas Machado AC, Guo M, Sagendorf JM, Zhou Z, Jiang L, Chen X, Wu D, Qu L, Chen Z et al (2017a) Structure of the forkhead domain of FOXA2 bound to a complete DNA consensus site. Biochemistry 56:3745–3753PubMedPubMedCentralGoogle Scholar
  20. Li D, He C, Wang J, Wang Y, Bu J, Kong X, Sun D (2017b) MicroRNA-138 inhibits cell growth, invasion and EMT of non-small cell lung cancer via SOX4/p53 feedback loop. Oncol Res 2017:385Google Scholar
  21. Li C, Lu S, Shi Y (2017c) MicroRNA-187 promotes growth and metastasis of gastric cancer by inhibiting FOXA2. Oncol Rep 37:1747–1755PubMedGoogle Scholar
  22. Liu S, Jiang Y, Yan R, Li Z, Wan S, Zhang T, Wu X, Hou J, Zhu Z, Tian Y, Zhang J (2015) Design, synthesis and biological evaluations of 2-amino-4-(1-piperidine) pyridine derivatives as novel anti crizotinib-resistant ALK/ROS1 dual inhibitors. Eur J Med Chem 1(179):358–375. (Epub 2019 Jun 25) CrossRefGoogle Scholar
  23. Liu Z, Zhao Y, Fang J, Cui R, Xiao Y, Xu Q (2017) SHP2 negatively regulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in prostate cancer cells. Oncotarget 8:53518–53530PubMedPubMedCentralGoogle Scholar
  24. Ma Y, Wu L, Liu X, Xu Y, Shi W, Liang Y, Yao L, Zheng J, Zhang J (2017) KLF4 inhibits colorectal cancer cell proliferation dependent on NDRG2 signaling. Oncol Rep 38:975–984PubMedGoogle Scholar
  25. McFadden VC, Shalaby RE, Iram S, Oropeza CE, Landolfi JA, Lyubimov AV, Maienschein-Cline M, Green SJ, Kaestner KH, McLachlan A (2017) Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation. PLoS Pathog 13:e1006239PubMedPubMedCentralGoogle Scholar
  26. Múnera JO, Sundaram N, Rankin SA, Hill D, Watson C, Mahe M, Vallance JE, Shroyer NF, Sinagoga KL, Zarzoso-Lacoste A et al (2017) Differentiation of human pluripotent stem cells into colonic organoids via transient activation of BMP signaling. Cell Stem Cell 21:51.e6–64.e6Google Scholar
  27. Myint ZW, Goel G (2017) Role of modern immunotherapy in gastrointestinal malignancies: a review of current clinical progress. J Hematol Oncol 10:86PubMedPubMedCentralGoogle Scholar
  28. Nakamura M, Tokura Y (2011) Epithelial-mesenchymal transition in the skin. J Dermatol Sci 61:7–13PubMedGoogle Scholar
  29. Nelson AC, Cutty SJ, Gasiunas SN, Deplae I, Stemple DL, Wardle FC (2017) In vivo regulation of the zebrafish endoderm progenitor niche by T-Box transcription factors. Cell Rep 19:2782–2795PubMedPubMedCentralGoogle Scholar
  30. Pahwa M, Harris MA, MacLeod J, Tjepkema M, Peters PA, Demers PA (2017) Sedentary work and the risks of colon and rectal cancer by anatomical sub-site in the Canadian census health and environment cohort (CanCHEC). Cancer Epidemiol 49:144–151PubMedGoogle Scholar
  31. Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G (1998) Acausal role for E-cadherin in the transition from adenoma tocarcinoma. Nature 392:190–193PubMedGoogle Scholar
  32. Rattan R, Ali Fehmi R, Munkarah A (2012) Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. J Oncol 928127:2012Google Scholar
  33. Rausa FM III, Hughes DE, Costa RH (2004) Stability of the hepatocyte nuclear factor 6 transcription factor requires acetylation by the CREB-binding protein coactivator. J Biol Chem 279:43070–43076PubMedGoogle Scholar
  34. Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J (2008) Epithelial–mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68:989–997PubMedGoogle Scholar
  35. Schayek H, Laitman Y, Katz LH, Pras E, Ries-Levavi L, Barak F, Friedman E (2017) Colorectal and endometrial cancer risk and age at diagnosis in BLMAsh mutation carriers. Isr Med Assoc J 19:365–367PubMedGoogle Scholar
  36. Seo HS, Ku JM, Choi HS, Woo JK, Lee BH, Kim DS, Song HJ, Jang BH, Shin YC, Ko SG (2017) Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells. Oncol Rep 38:715–724PubMedPubMedCentralGoogle Scholar
  37. Shen Y, Nar R, Fan AX, Aryan M, Hossain MA, Gurumurthy A, Wassel PC, Tang M, Lu J, Strouboulis J, Bungert J (2018) Functional interrelationship between TFII–I and E2F transcription factors at specific cell cycle gene loci. J Cell Biochem 119:712–722PubMedGoogle Scholar
  38. Stein U, Walther W, Arlt F, Schwabe H, Smith J, Fichtner I, Birchmeier W, Schlag PM (2009) MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 15:59–67PubMedGoogle Scholar
  39. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial–mesenchymal transitions in development and disease. Cell 139:871–890PubMedPubMedCentralGoogle Scholar
  40. Tu MJ, Pan YZ, Qiu JX, Kim EJ, Yu AM (2016) MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis. Oncotarget 7:45547–45561PubMedPubMedCentralGoogle Scholar
  41. Von Stetina SE, Liang J, Marnellos G, Mango SE (2017) Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6. Mol Biol Cell 28:2042–2065Google Scholar
  42. Wahl GM, Spike BT (2017) Cell state plasticity, stem cells, EMT, and the generation of intra-tumoral heterogeneity. NPJ Breast Cancer 3:14PubMedPubMedCentralGoogle Scholar
  43. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939Google Scholar
  44. Zhang L, Rubins NE, Ahima RS, Greenbaum LE, Kaestner KH (2005) Foxa2 integrates the transcriptional response of the hepatocyte to fasting. Cell Metab 2:141–148PubMedGoogle Scholar
  45. Zhou Q, Dai J, Chen T, Dada LA, Zhang X, Zhang W, DeCamp MM, Winn RA, Sznajder JI, Zhou G (2017) Downregulation of PKCζ/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion. Cell Signal 38:49–59PubMedPubMedCentralGoogle Scholar

Copyright information

© King Abdulaziz City for Science and Technology 2019

Authors and Affiliations

  1. 1.Department of GastroenterologyBinzhou Center HospitalBinzhouPeople’s Republic of China
  2. 2.Department of OncologyJinan Central HospitalJinanPeople’s Republic of China

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