International Journal of Oral Biology

The Korean Academy of Oral Biology (대한구강생물학회)
권호 표지
DOI QR코드

DOI QR Code

Luteolin Induces Apoptosis via Mitochondrial Pathway and Inhibits Invasion and Migration of Oral Squamous Cell Carcinoma by Suppressing Epithelial-Mesenchymal Transition Induced Transcription Factors

  • Park, Bong-Soo (Department of Oral Anatomy, School of Dentistry, Pusan National University) ;
  • Kil, Jong-Jin (Department of Oral Anatomy, School of Dentistry, Pusan National University) ;
  • Kang, Hae-Mi (Department of Oral Anatomy, School of Dentistry, Pusan National University) ;
  • Yu, Su-Bin (Department of Oral Anatomy, School of Dentistry, Pusan National University) ;
  • Park, Dan-Bi (Department of Oral Anatomy, School of Dentistry, Pusan National University) ;
  • Park, Jin-A (Department of Oral Anatomy, School of Dentistry, Pusan National University) ;
  • Kim, In-Ryoung (Department of Oral Anatomy, School of Dentistry, Pusan National University)
  • Received : 2018.05.28
  • Accepted : 2018.06.14
  • Published : 2018.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Oral squamous cell carcinoma (OSCC) is the most common type of oral malignancy. Numerous therapies have been proposed for its cure. Research is continually being conducted to develop new forms of treatment as current therapies are associated with numerous side-effects. Luteolin, a common dietary flavonoid, has been demonstrated to possess strong anti-cancer activity against various human cancer cell lines. Nevertheless, research into luteolin-based anticancer activity against oral cancer remains scarce. Thus, the objective of this study was to assess the effect of luteolin as an anti-cancer agent. After treatment with luteolin, Ca9-22 and CAL-27 oral cancer cells showed condensed nuclei and enhanced apoptotic rate with evidence of mitochondria-mediated apoptosis. Epithelialmesenchymal transition (EMT) is closely related to tumor migration and invasion. Luteolin suppressed cancer cell invasion and migration in the current study. Elevated expression of E-cadherin, an adherens junction protein, was evident in both cell lines after luteolin treatment. Luteolin also significantly inhibited transcription factors (i.e., N-cadherin, Slug, Snail, Twist, and ZEB-1) that regulated expression of tumor suppressors such as E-cadherin based on Western blot analysis and quantitative PCR. Thus, luteolin could induce mitochondrial apoptosis and inhibit cancer cell invasion and migration by suppressing EMT-induced transcription factors.

Keywords

References

  1. Ishida T, Hijioka H, Kume K, Miyawaki A, Nakamura N. Notch signaling induces EMT in OSCC cell lines in a hypoxic environment. Oncol Lett 2013;6:1201-1206. https://doi.org/10.3892/ol.2013.1549
  2. Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol 2009;45:301-308. https://doi.org/10.1016/j.oraloncology.2009.01.004
  3. Li C, Yazawa K, Kondo S, Mukudai Y, Sato D, Kurihara Y, Kamatani T, Shintani S. The root bark of Paeonia moutan is a potential anticancer agent in human oral squamous cell carcinoma cells. Anticancer research 2012;32:2625-2630.
  4. Petersen PE, Bourgeois D, Bratthall D, Ogawa H. Oral health information systems-towards measuring progress in oral health promotion and disease prevention. Bulletin of the World Health Organization 2005;83:686-693.
  5. Reid BC, Rozier RG. Continuity of care and early diagnosis of head and neck cancer. Oral oncology 2006;42:510-516. https://doi.org/10.1016/j.oraloncology.2005.10.009
  6. Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacology & therapeutics 2001;90:157-177. https://doi.org/10.1016/S0163-7258(01)00137-1
  7. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annual review of nutrition 2002;22:19-34. https://doi.org/10.1146/annurev.nutr.22.111401.144957
  8. Miean KH, Mohamed S. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. Journal of agricultural and food chemistry 2001;49: 3106-3112. https://doi.org/10.1021/jf000892m
  9. Sun T, Xu Z, Wu CT, Janes M, Prinyawiwatkul W, No H. Antioxidant activities of different colored sweet bell peppers (Capsicum annuum L.). Journal of Food Science 2007;72.
  10. Shi RX, Ong CN, Shen HM. Protein kinase C inhibition and x-linked inhibitor of apoptosis protein degradation contribute to the sensitization effect of luteolin on tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cancer cells. Cancer Res 2005;65:7815-7823. https://doi.org/10.1158/0008-5472.CAN-04-3875
  11. Lim DY, Jeong Y, Tyner AL, Park JH. Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am J Physiol Gastrointest Liver Physiol 2007;292:G66-75. https://doi.org/10.1152/ajpgi.00248.2006
  12. Fang J, Zhou Q, Shi XL, Jiang BH. Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells. Carcinogenesis 2007;28:713-723.
  13. Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, Kandaswami C, Middleton E, Lee MT. Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. British journal of pharmacology 1999;128:999-1010. https://doi.org/10.1038/sj.bjp.0702879
  14. Ko W, Kang T, Lee S, Kim Y, Lee B. Effects of luteolin on the inhibition of proliferation and induction of apoptosis in human myeloid leukaemia cells. Phytotherapy Research 2002;16:295-298. https://doi.org/10.1002/ptr.871
  15. Haddad A, Venkateswaran V, Viswanathan L, Teahan S, Fleshner N, Klotz L. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate cancer and prostatic diseases 2006;9:68. https://doi.org/10.1038/sj.pcan.4500845
  16. Tjioe KC, Tostes Oliveira D, Gavard J. Luteolin impacts on the DNA damage pathway in oral squamous cell carcinoma. Nutrition and cancer 2016;68:838-847. https://doi.org/10.1080/01635581.2016.1180411
  17. Loro LL, Vintermyr OK, Liavaag PG, Jonsson R, Johannessen AC. Oral squamous cell carcinoma is associated with decreased bcl-2/bax expression ratio and increased apoptosis. Human pathology 1999;30:1097-1105. https://doi.org/10.1016/S0046-8177(99)90229-0
  18. Ahn G, Lee W, Kim K-N, Lee J-H, Heo S-J, Kang N, Lee S-H, Ahn C-B, Jeon Y-J. A sulfated polysaccharide of Ecklonia cava inhibits the growth of colon cancer cells by inducing apoptosis. EXCLI journal 2015;14:294.
  19. Dia VP, Pangloli P. Epithelial-to-Mesenchymal Transition in Paclitaxel-Resistant Ovarian Cancer Cells Is Downregulated by Luteolin. J Cell Physiol 2017;232:391-401. https://doi.org/10.1002/jcp.25436
  20. Weinberg RA. Twisted epithelial-mesenchymal transition blocks senescence. Nature Cell Biology 2008;10:1021. https://doi.org/10.1038/ncb0908-1021
  21. Hennessy BT, Gonzalez-Angulo A-M, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee J-S, Fridlyand J, Sahin A, Agarwal R, Joy C. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer research 2009;69:4116-4124.
  22. Kong D, Li Y, Wang Z, Sarkar F. Cancer Stem Cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins? Cancers 2011;3:716. https://doi.org/10.3390/cancers30100716
  23. da Silva SD, Morand GB, Alobaid FA, Hier MP, Mlynarek AM, Alaoui-Jamali MA, Kowalski LP. Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma. Clinical & Experimental Metastasis 2015;32: 55-63. https://doi.org/10.1007/s10585-014-9690-1
  24. Zhou J-P, Gao Z-L, Zhou M-L, He M-Y, Xu X-H, Tao D-T, Yang C-C, Liu L-K. Snail interacts with Id2 in the regulation of TNF-${\alpha}$-induced cancer cell invasion and migration in OSCC. American journal of cancer research 2015;5:1680.
  25. Yu C-C, Chen P-N, Peng C-Y, Yu C-H, Chou M-Y. Suppression of miR-204 enables oral squamous cell carcinomas to promote cancer stemness, EMT traits, and lymph node metastasis. Oncotarget 2016;7:20180.
  26. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010;29:4741. https://doi.org/10.1038/onc.2010.215
  27. Kim IR, Kim SE, Baek HS, Kim BJ, Kim CH, Chung IK, Park BS, Shin SH. The role of kaempferol-induced autophagy on differentiation and mineralization of osteoblastic MC3T3-E1 cells. BMC complementary and alternative medicine 2016;16:333. https://doi.org/10.1186/s12906-016-1320-9
  28. Sun J, Shi X, Li S, Piao F. 2,5-hexanedione induces bone marrow mesenchymal stem cell apoptosis via inhibition of Akt/Bad signal pathway. J Cell Biochem 2017.
  29. Morales J, Li L, Fattah FJ, Dong Y, Bey EA, Patel M, Gao J, Boothman DA. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Critical ReviewsTM in Eukaryotic Gene Expression 2014;24.
  30. Torres MP, Rachagani S, Souchek JJ, Mallya K, Johansson SL, Batra SK. Novel pancreatic cancer cell lines derived from genetically engineered mouse models of spontaneous pancreatic adenocarcinoma: applications in diagnosis and therapy. PLoS One 2013;8:e80580. https://doi.org/10.1371/journal.pone.0080580
  31. Kojc N, Zidar N, Gale N, Poljak M, Fujs Komlos K, Cardesa A, Hofler H, Becker KF. Transcription factors Snail, Slug, Twist, and SIP1 in spindle cell carcinoma of the head and neck. Virchows Arch 2009;454:549-555. https://doi.org/10.1007/s00428-009-0771-5
  32. Wu J-Y, Yi C, Chung H-R, Wang D-J, Chang W-C, Lee S-Y, Lin C-T, Yang Y-C, Yang W-CV. Potential biomarkers in saliva for oral squamous cell carcinoma. Oral oncology 2010;46:226-231. https://doi.org/10.1016/j.oraloncology.2010.01.007
  33. Marocchio LS, Lima J, Sperandio FF, Correa L, Sousa SOd. Oral squamous cell carcinoma: an analysis of 1,564 cases showing advances in early detection. Journal of oral science 2010;52:267-273. https://doi.org/10.2334/josnusd.52.267
  34. Rates SMK. Plants as source of drugs. Toxicon 2001;39:603-613. https://doi.org/10.1016/S0041-0101(00)00154-9
  35. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. The Scientific World Journal 2013;2013.
  36. Balunas MJ, Kinghorn AD. Drug discovery from medicinal plants. Life sciences 2005;78:431-441. https://doi.org/10.1016/j.lfs.2005.09.012
  37. Ueda H, Yamazaki C, Yamazaki M. Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla frutescens. Biological and Pharmaceutical Bulletin 2002;25:1197-1202. https://doi.org/10.1248/bpb.25.1197
  38. Seelinger G, Merfort I, Schempp CM. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta medica 2008;74:1667-1677. https://doi.org/10.1055/s-0028-1088314
  39. Seelinger G, Merfort I, Wolfle U, Schempp CM. Anticarcinogenic effects of the flavonoid luteolin. Molecules 2008;13:2628-2651. https://doi.org/10.3390/molecules13102628
  40. Huang HW, Chung YA, Chang HS, Tang JY, Chen IS, Chang HW. Antiproliferative effects of methanolic extracts of Cryptocarya concinna Hance roots on oral cancer Ca9-22 and CAL 27 cell lines involving apoptosis, ROS induction, and mitochondrial depolarization. ScientificWorldJournal 2014;2014:180462.
  41. Cohen G, Sun X, Snowden R, Dinsdale D, Skilleter D. Key morphological features of apoptosis may occur in the absence of internucleosomal DNA fragmentation. Biochemical Journal 1992;286:331-334. https://doi.org/10.1042/bj2860331
  42. Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nature reviews Molecular cell biology 2010;11:621-632. https://doi.org/10.1038/nrm2952
  43. Kang MH, Reynolds CP. Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy. Clinical Cancer Research 2009;15:1126-1132. https://doi.org/10.1158/1078-0432.CCR-08-0144
  44. Kim H-E, Jiang X, Du F, Wang X. PHAPI, CAS, and Hsp70 Promote Apoptosome Formation by Preventing Apaf-1 Aggregation and Enhancing Nucleotide Exchange on Apaf-1. Molecular Cell 2008;30:239-247. https://doi.org/10.1016/j.molcel.2008.03.014
  45. Kim CH, Ko AR, Lee SY, Jeon HM, Kim SM, Park HG, Han SI, Kang HS. Hypoxia switches glucose depletion-induced necrosis to phosphoinositide 3-kinase/Akt-dependent apoptosis in A549 lung adenocarcinoma cells. International journal of oncology 2010;36:117.
  46. Biddle A, Mackenzie IC. Cancer stem cells and EMT in carcinoma. Cancer and Metastasis Reviews 2012;31:285-293. https://doi.org/10.1007/s10555-012-9345-0
  47. Wells A, Yates C, Shepard CR. E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 2008;25:621-628. https://doi.org/10.1007/s10585-008-9167-1
  48. Shin NR, Jeong EH, Choi CI, Moon HJ, Kwon CH, Chu IS, Kim GH, Jeon TY, Kim DH, Lee JH. Overexpression of Snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer. BMC cancer 2012;12:1. https://doi.org/10.1186/1471-2407-12-1
  49. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. Journal of cell science 2003;116:499-511. https://doi.org/10.1242/jcs.00224
  50. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. The Journal of clinical investigation 2009;119:1429-1437. https://doi.org/10.1172/JCI36183
  51. Shankar S, Nall D, Tang S-N, Meeker D, Passarini J, Sharma J, Srivastava RK. Resveratrol inhibits pancreatic cancer stem cell characteristics in human and Kras G12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One 2011;6:e16530. https://doi.org/10.1371/journal.pone.0016530
  52. Tania M, Khan MA, Fu J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer. Tumor Biology 2014;35:7335-7342. https://doi.org/10.1007/s13277-014-2163-y
  53. Lu Q, Ji X-J, Zhou Y-X, Yao X-Q, Liu Y-Q, Zhang F, Yin X-X. Quercetin inhibits the mTORC1/p70S6K signaling- mediated renal tubular epithelial-mesenchymal transition and renal fibrosis in diabetic nephropathy. Pharmacological research 2015;99:237-247. https://doi.org/10.1016/j.phrs.2015.06.006