Skip to main content

Advertisement

SpringerLink
Log in

Chlorogenic acid regulates apoptosis and stem cell marker-related gene expression in A549 human lung cancer cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Previous studies indicated that chlorogenic acid, a compound present in many fruits and vegetables, has anti-cancer activities. We report that chlorogenic acid regulates the expression of apoptosis-related genes and self-renewal-related stem cell markers in cancer cells. The lung cancer cell line A549 was cultured with or without chlorogenic acid. The presence of chlorogenic acid decreased cell proliferation as measured by MTT activity. Polymerase chain reaction (PCR) showed that treatment of cells with chlorogenic acid reduced the expression of BCL2 but increased that of both BAX and CASP3. Chlorogenic acid enhanced annexin V expression as measured using fluorescently labeled annexin V. Chlorogenic acid also induced p38 MAPK and JNK gene expression. Meanwhile, several agents, including SB203580 (p38 MAP kinase inhibitor), N-acetylcysteine (antioxidant inhibitor), dipyridamole (phosphodiesterase inhibitor), and apocynin (NADPH-oxidase inhibitor) blocked chlorogenic acid-induced BAX gene expression. Chlorogenic acid reduced gene expression levels of stem cell-associated markers NANOG, POU5F1, and SOX2. Together these results indicate that chlorogenic acid affects the expression of apoptosis-related genes that are part of oxidative stress and p38 MAP-dependent pathways, as well as genes encoding stem cell markers. In conclusion, chlorogenic acid may contribute to the polyphenolic anti-cancer effect associated with consumption of vegetables and fruits.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

CSCs:

Cancer stem cells

NAC:

N-acetylcysteine

NSCLC:

Non-small cell lung cancer

ROS:

Reactive oxygen species (ROS)

References

  1. Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ et al (2004) American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22:330–353

    Article  PubMed  Google Scholar 

  2. Gatof D, Ahnen D (2002) Primary prevention of colorectal cancer: diet and drugs. Gastroenterol Clin North Am 31:587–623

    Article  PubMed  Google Scholar 

  3. Harper CE, Patel BB, Wang J, Arabshahi A, Eltoum IA et al (2007) Resveratrol suppresses prostate cancer progression in transgenic mice. Carcinogenesis 28:1946–1953

    Article  CAS  PubMed  Google Scholar 

  4. Li MJ, Yin YC, Wang J, Jiang YF (2014) Green tea compounds in breast cancer prevention and treatment. World J Clin Oncol 5:520–528

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ogawa T, Sawada N, Iwasaki M, Budhathoki S, Hidaka A et al (2016) Coffee and green tea consumption in relation to brain tumor risk in a Japanese population. Int J Cancer 139:2714–2721

    Article  CAS  PubMed  Google Scholar 

  6. Larsson SC, Giovannucci EL, Wolk A (2017) Coffee consumption and risk of gallbladder cancer in a prospective study. J Natl Cancer Inst 109:1–3

    Article  PubMed  Google Scholar 

  7. Fabiani R, Minelli L, Rosignoli P (2016) Apple intake and cancer risk: a systematic review and meta-analysis of observational studies. Public Health Nutr 19:2603–2617

    Article  PubMed  Google Scholar 

  8. Hou N, Liu N, Han J, Yan Y, Li J (2017) Chlorogenic acid induces reactive oxygen species generation and inhibits the viability of human colon cancer cells. Anticancer Drugs 28:59–65

    Article  CAS  PubMed  Google Scholar 

  9. Vitaglione P, Fogliano V, Pellegrini N (2012) Coffee, colon function and colorectal cancer. Food Funct 3:916–922

    Article  CAS  PubMed  Google Scholar 

  10. Huang MT, Smart RC, Wong CQ, Conney AH (1988) Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 48:5941–5946

    CAS  PubMed  Google Scholar 

  11. Kasai H, Fukada S, Yamaizumi Z, Sugie S, Mori H (2000) Action of chlorogenic acid in vegetables and fruits as an inhibitor of 8-hydroxydeoxyguanosine formation in vitro and in a rat carcinogenesis model. Food Chem Toxicol 38:467–471

    Article  CAS  PubMed  Google Scholar 

  12. D’Archivio M, Filesi C, Di Benedetto R, Gargiulo R, Giovannini C et al (2007) Polyphenols, dietary sources and bioavailability. Ann Ist Super Sanita 43:348–361

    PubMed  Google Scholar 

  13. Guchelaar HJ, Vermes A, Vermes I, Haanen C (1997) Apoptosis: molecular mechanisms and implications for cancer chemotherapy. Pharm World Sci 19:119–125

    Article  CAS  PubMed  Google Scholar 

  14. Boise LH, Gottschalk AR, Quintans J, Thompson CB (1995) Bcl-2 and Bcl-2-related proteins in apoptosis regulation. Curr Top Microbiol Immunol 200:107–121

    CAS  PubMed  Google Scholar 

  15. Karunagaran D, Rashmi R, Kumar TR (2005) Induction of apoptosis by curcumin and its implications for cancer therapy. Curr Cancer Drug Targets 5:117–129

    Article  CAS  PubMed  Google Scholar 

  16. Shankar S, Srivastava RK (2007) Bax and Bak genes are essential for maximum apoptotic response by curcumin, a polyphenolic compound and cancer chemopreventive agent derived from turmeric, Curcuma longa. Carcinogenesis 28:1277–1286

    Article  CAS  PubMed  Google Scholar 

  17. Liu YJ, Zhou CY, Qiu CH, Lu XM, Wang YT (2013) Chlorogenic acid induced apoptosis and inhibition of proliferation in human acute promyelocytic leukemia HL-60 cells. Mol Med Rep 8:1106–1110

    Article  CAS  PubMed  Google Scholar 

  18. Yang JS, Liu CW, Ma YS, Weng SW, Tang NY, Wu SH, Ji BC, Ma CY, Ko YC, Funayama S, Kuo CL (2012) Chlorogenic acid induces apoptotic cell death in U937 leukemia cells through caspase- and mitochondria-dependent pathways. In Vivo 26:971–978

    CAS  PubMed  Google Scholar 

  19. Ramos S (2008) Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Mol Nutr Food Res 52:507–526

    Article  CAS  PubMed  Google Scholar 

  20. Meacham CE, Morrison SJ (2013) Tumour heterogeneity and cancer cell plasticity. Nature 501:328–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mitra A, Mishra L, Li S (2015) EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget 6:10697–10711

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bourguignon LY, Gilad E, Brightman A, Diedrich F, Singleton P (2006) Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells. J Biol Chem 281:14026–14040

    Article  CAS  PubMed  Google Scholar 

  23. Paul I, Jones JM (2014) Apoptosis block as a barrier to effective therapy in non small cell lung cancer. World J Clin Oncol 5:588–594

    Article  PubMed  PubMed Central  Google Scholar 

  24. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mack B, Gires O (2008) CD44s and CD44v6 expression in head and neck epithelia. PLoS ONE 3:e3360

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642

    Article  CAS  PubMed  Google Scholar 

  27. Bourguignon LY, Xia W, Wong G (2009) Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates β-catenin signaling and NFκB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells. J Biol Chem 284:2657–2671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gontan C, de Munck A, Vermeij M, Grosveld F, Tibboel D, Rottier R (2008) Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation. Develop Biol 317:296–309

    Article  CAS  PubMed  Google Scholar 

  29. Liu K, Xie F, Gao A, Zhang R, Zhang L, Xiao Z, Hu Q, Huang W, Huang Q, Lin B, Zhu J, Wang H, Que J, Lan X (2017) SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis. Mol Cancer 16:62

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wang X, Dai J (2010) Concise review. Isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem Cells 28:885–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Gudas LJ, Mongan NP (2009) Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev 18:1093–1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu CP, Du HD, Gong HL, Li DW, Tao L, Tian J, Zhou L (2014) Hypoxia promotes stem-like properties of laryngeal cancer cell lines by increasing the CD133+ stem cell fraction. Int J Oncol 44:1652–1660

    Article  CAS  PubMed  Google Scholar 

  33. Opipari AW, Tan L, Boitano AE, Sorenson DR, Liu Aurora A (2004) Resveratrol-induced autophagocytosis in ovarian cancer cells. Cancer Res 64:696–703

    Article  CAS  PubMed  Google Scholar 

  34. Lee YJ, Kim NY, Suh YA, Lee C (2011) Involvement of ROS in curcumin-induced autophagic cell death. Korean J Physiol Pharmacol 15:1–7

    Article  PubMed  PubMed Central  Google Scholar 

  35. Seo HS, Ku JM, Choi HS, Woo JK, Jang BH, Go H, Shin YC, Ko SG (2015) Apigenin induces caspase-dependent apoptosis by inhibiting signal transducer and activator of transcription 3 signaling in HER2-overexpressing SKBR3 breast cancer cells. Mol Med Rep 12:2977–2984

    Article  CAS  PubMed  Google Scholar 

  36. Chen J, Duan Y, Zhang X, Ye Y, Ge B, Chen J (2015) Genistein induces apoptosis by the inactivation of the IGF-1R/p-Akt signaling pathway in MCF-7 human breast cancer cells. Food Funct 6:995–1000

    Article  CAS  PubMed  Google Scholar 

  37. Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS (2010) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 16:2580–2590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Guo Y, Chang H, Li J, Xu XY, Shen L, Yu ZB, Liu WC (2015) Thymosin alpha 1 suppresses proliferation and induces apoptosis in breast cancer cells through PTEN-mediated inhibition of PI3K/Akt/mTOR signaling pathway. Apoptosis 20:1109–1121

    Article  CAS  PubMed  Google Scholar 

  39. Wang M, Zhang C, Song Y, Wang Z, Wang Y, Luo F, Xu Y, Zhao Y, Wu Z, Xu Y (2017) Mechanism of immune evasion in breast cancer. Onco Targets Ther 10:1561–1573

    Article  PubMed  PubMed Central  Google Scholar 

  40. Reed JC, Miyashita T, Takayama S, Wang HG, Sato T, Krajewski S, Aime-Sempe C, Bodrug S, Kitada S, Hanada M (1996) BCL-2 family proteins: regulators of cell death involved in the pathogenesis of cancer and resistance to therapy. J Cell Biochem 60:23–32

    Article  CAS  PubMed  Google Scholar 

  41. Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ (1995) Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci USA 92:7834–7838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pepper C, Hoy T, Bentley P (1998) Elevated Bcl-2/Bax are a consistent feature of apoptosis resistance in B-cell chronic lymphocytic leukaemia and are correlated with in vivo chemoresistance. Leuk Lymphoma 28:355–361

    Article  CAS  PubMed  Google Scholar 

  43. Del Principe MI, Dal Bo M, Bittolo T, Buccisano F, Rossi FM et al (2016) Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia. Haematologica 101:77–85

    Article  PubMed  PubMed Central  Google Scholar 

  44. Yao Q, Lin M, Wang Y, Lai Y, Hu J, Fu T, Wang L, Lin S, Chen L, Guo Y (2015) Curcumin induces the apoptosis of A549 cells via oxidative stress and MAPK signaling pathways. Int J Mol Med 36:1118–1126

    Article  PubMed  Google Scholar 

  45. Pollier J, Goossens A (2012) Oleanolic acid. Phytochemistry 77:10–15

    Article  CAS  PubMed  Google Scholar 

  46. Liu J, Wu N, Ma LN, Zhong JT, Liu G, Zheng LH, Lin XK (2014) p38 MAPK signaling mediates mitochondrial apoptosis in cancer cells induced by oleanolic acid. Asian Pac J Cancer Prev 15:4519–4525

    Article  PubMed  Google Scholar 

  47. Erdogan S, Doganlar O, Doganlar ZB, Serttas R, Turkekul K, Dibirdik I, Bilir A (2016) The flavonoid apigenin reduces prostate cancer CD44(+) stem cell survival and migration through PI3K/Akt/NF-κB signaling. Life Sci 162:77–86

    Article  CAS  PubMed  Google Scholar 

  48. MacDonagh L, Gray SG, Breen E, Cuffe S, Finn SP, O’Byrne KJ, Barr MP (2016) Lung cancer stem cells: the root of resistance. Cancer Lett 372:147–156

    Article  CAS  PubMed  Google Scholar 

  49. Yamagata K, Sone N, Suguyama S, Nabika T (2016) Different effects of arginine vasopressin on high-mobility group box 1 expression in astrocytes isolated from stroke-prone spontaneously hypertensive rats and congenic SHRpch1_18 rats. Int J Exp Pathol 97:97–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yamagata K, Yamamoto M, Kawakami K, Ohara H, Nabika T (2014) Arginine vasopressin regulated ASCT1 expression in astrocytes from stroke-prone spontaneously hypertensive rats and congenic SHRpch1_18 rats. Neuroscience 267:277–285

    Article  CAS  PubMed  Google Scholar 

  51. Gibson UE, Heid CA, Williams PM (1996) A novel method for real time quantitative RT-PCR. Genome Res 6:996–1001

    Article  Google Scholar 

  52. Rissoan MC, Soumelis V, Kadowaki N, Grouard G, Briere F, de Waal Malefyt R, Liu YJ (1999) Reciprocal control of T helper cell and dendritic cell differentiation. Science 283:1183–1186

    Article  CAS  PubMed  Google Scholar 

  53. Yamagata K, Tanaka N, Suzuki K (2013) Epigallocatechin 3-gallate inhibits 7-ketocholesterol-induced monocyte-endothelial cell adhesion. Microvasc Res 88:25–31

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Health Science of Food, Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), 1866, Kameino, Fujisawa, Kanagawa, 252-8510, Japan

    Kazuo Yamagata, Yuri Izawa & Daiki Onodera

  2. Department of Internal Medicine, Sanraku Hospital, Chiyoda-Ku, Tokyo, Japan

    Motoki Tagami

Authors
  1. Kazuo Yamagata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuri Izawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daiki Onodera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Motoki Tagami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazuo Yamagata.

Ethics declarations

Conflicts of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamagata, K., Izawa, Y., Onodera, D. et al. Chlorogenic acid regulates apoptosis and stem cell marker-related gene expression in A549 human lung cancer cells. Mol Cell Biochem 441, 9–19 (2018). https://doi.org/10.1007/s11010-017-3171-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-3171-1

Keywords

Search

Navigation