DOI QR코드

DOI QR Code

Menadione (Vitamin K3) Induces Apoptosis of Human Oral Cancer Cells and Reduces their Metastatic Potential by Modulating the Expression of Epithelial to Mesenchymal Transition Markers and Inhibiting Migration

  • Suresh, Shruthy (Department of Biotechnology, Indian Institute of Technology Madras) ;
  • Raghu, Dinesh (Department of Biotechnology, Indian Institute of Technology Madras) ;
  • Karunagaran, Devarajan (Department of Biotechnology, Indian Institute of Technology Madras)
  • 발행 : 2013.09.30

초록

Oral cancer is one of the most commonly occurring cancers worldwide, decreasing the patient's survival rate due to tumor recurrence and metastasis. Menadione (Vitamin K3) is known to exhibit cytotoxicity in various cancer cells but the present study focused on its effects on viability, apoptosis, epithelial to mesenchymal transition (EMT), anchorage independent growth and migration of oral cancer cells. The results show that menadione is more cytotoxic to SAS (oral squamous carcinoma) cells but not to non-tumorigenic HEK293 and HaCaT cells. Menadione treatment increased the expression of pro-apoptotic proteins, Bax and p53, with a concurrent decrease in anti-apoptotic proteins, Bcl-2 and p65. Menadione induced the expression of E-cadherin but reduced the expression of EMT markers, vimentin and fibronectin. Menadione also inhibited anchorage independent growth and migration in SAS cells. These findings reveal and confirm that menadione is a potential candidate in oral cancer therapy as it exhibits cytotoxic, antineoplastic and antimigratory effects besides effectively blocking EMT in oral cancer cells.

키워드

참고문헌

  1. Alderton GK (2013). Metastasis: epithelial to mesenchymal and back again. Nat Rev Cancer, 13, 3. https://doi.org/10.1038/nrc3428
  2. Arumugam T, Ramachandran V, Fournier KF, et al (2009). Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res, 69, 5820-8. https://doi.org/10.1158/0008-5472.CAN-08-2819
  3. Byakodi R, Byakodi S, Hiremath S, et al (2012). Oral cancer in India: an epidemiologic and clinical review. J Community Health, 37, 316-9. https://doi.org/10.1007/s10900-011-9447-6
  4. Chiou TJ, Tzeng WF (2000). The roles of glutathione and antioxidant enzymes in menadione-induced oxidative stress. Toxicology, 154, 75-84. https://doi.org/10.1016/S0300-483X(00)00321-8
  5. Cranenburg EC, Schurgers LJ, Vermeer C (2007). Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost, 98, 120-5.
  6. Delwar ZM, Siden A, Cruz MH, Yakisich JS (2012). Menadione: sodium orthovanadate combination eliminates and inhibits migration of detached cancer cells. ISRN pharmacology, 2012, 307102.
  7. Forastiere A, Koch W, Trotti A, Sidransky D (2001). Head and neck cancer. N Engl J Med, 345, 1890-900. https://doi.org/10.1056/NEJMra001375
  8. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C (2006). Clonogenic assay of cells in vitro. Nat Protoc, 1, 2315-9. https://doi.org/10.1038/nprot.2006.339
  9. Hassan GS (2013). Menadione. Profiles Drug Subst Excip Relat Methodol, 38, 227-313. https://doi.org/10.1016/B978-0-12-407691-4.00006-X
  10. Hsu S, Singh B, Schuster G (2004). Induction of apoptosis in oral cancer cells: agents and mechanisms for potential therapy and prevention. Oral Oncol, 40, 461-73. https://doi.org/10.1016/j.oraloncology.2003.09.012
  11. Kitano T, Yoda H, Tabata K, et al (2012). Vitamin K3 analogs induce selective tumor cytotoxicity in neuroblastoma. Biol Pharm Bull, 35, 617-23. https://doi.org/10.1248/bpb.35.617
  12. Krisanaprakornkit S, Iamaroon A (2012). Epithelialmesenchymal transition in oral squamous cell carcinoma. ISRN Oncol, 2012, 681469.
  13. Liang CC, Park AY, Guan JL (2007). In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc, 2, 329-33. https://doi.org/10.1038/nprot.2007.30
  14. Mao L, Hong WK, Papadimitrakopoulou VA (2004). Focus on head and neck cancer. Cancer Cell, 5, 311-6. https://doi.org/10.1016/S1535-6108(04)00090-X
  15. McConkey DJ, Choi W, Marquis L, et al (2009). Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev, 28, 335-44. https://doi.org/10.1007/s10555-009-9194-7
  16. Na YR, Han KC, Park H, Yang EG (2013). Menadione and ethacrynic acid inhibit the hypoxia-inducible factor (HIF) pathway by disrupting HIF-1alpha interaction with p300. Biochem Biophys Res Comm, 434, 879-84. https://doi.org/10.1016/j.bbrc.2013.04.044
  17. Nakayama H, Ikebe T, Beppu M, Shirasuna K (2001). High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer, 92, 3037-44. https://doi.org/10.1002/1097-0142(20011215)92:12<3037::AID-CNCR10171>3.0.CO;2-#
  18. Nurwidya F, Takahashi F, Murakami A, Takahashi K (2012). Epithelial mesenchymal transition in drug resistance and metastasis of lung cancer. Cancer Res Treat, 44, 151-6. https://doi.org/10.4143/crt.2012.44.3.151
  19. Oh SJ, Han HK, Kang KW, Lee YJ, Lee MY (2013). Menadione serves as a substrate for P-glycoprotein: implication in chemosensitizing activity. Arch Pharm Res, 36, 509-516. https://doi.org/10.1007/s12272-013-0052-3
  20. Osada S, Tomita H, Tanaka Y, et al (2008). The utility of vitamin K3 (menadione) against pancreatic cancer. Anticancer Res, 28, 45-50.
  21. Park J, Schwarzbauer JE (2013). Mammary epithelial cell interactions with fibronectin stimulate epithelialmesenchymal transition. Oncogene, [Epub ahead of print].
  22. Sulkowska M, Famulski W, Sulkowski S, et al (2003). Correlation between Bcl-2 protein expression and some clinicopathological features of oral squamous cell carcinoma. Pol J Pathol, 54, 49-52.
  23. Teni T, Pawar S, Sanghvi V, Saranath D (2002). Expression of Bcl-2 and Bax in chewing tobacco-induced oral cancers and oral lesions from India. Pathol Oncol Res, 8, 109-14. https://doi.org/10.1007/BF03033719
  24. Thompson EW, Newgreen DF, Tarin D (2005). Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res, 65, 5991-5.
  25. Vermeer C, Shearer MJ, Zittermann A, et al (2004). Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health. Eur J Nutr, 43, 325-35. https://doi.org/10.1007/s00394-004-0480-4
  26. Verrax J, Cadrobbi J, Marques C, et al (2004). Ascorbate potentiates the cytotoxicity of menadione leading to an oxidative stress that kills cancer cells by a non-apoptotic caspase-3 independent form of cell death. Apoptosis, 9, 223-233. https://doi.org/10.1023/B:APPT.0000018804.26026.1a
  27. Wilkie-Grantham RP, Matsuzawa S, Reed JC (2013). Novel phosphorylation and ubiquitination sites regulate reactive oxygen species-dependent degradation of anti-apoptotic c-FLIP protein. J Biol Chem, 288, 12777-90. https://doi.org/10.1074/jbc.M112.431320
  28. Xie X, Clausen OP, De Angelis P, Boysen M (1999). The prognostic value of spontaneous apoptosis, Bax, Bcl-2, and p53 in oral squamous cell carcinoma of the tongue. Cancer, 86, 913-20. https://doi.org/10.1002/(SICI)1097-0142(19990915)86:6<913::AID-CNCR4>3.0.CO;2-A
  29. Yamamoto G, Irie T, Aida T, et al (2006). Correlation of invasion and metastasis of cancer cells, and expression of the RAD21 gene in oral squamous cell carcinoma. Virchows Arch, 448, 435-41. https://doi.org/10.1007/s00428-005-0132-y

피인용 문헌

  1. Ganoderma Lucidum Polysaccharides Target a Fas/Caspase Dependent Pathway to Induce Apoptosis in Human Colon Cancer Cells vol.15, pp.9, 2014, https://doi.org/10.7314/APJCP.2014.15.9.3981
  2. PRX1 knockdown potentiates vitamin K3 toxicity in cancer cells: a potential new therapeutic perspective for an old drug vol.34, pp.1, 2015, https://doi.org/10.1186/s13046-015-0270-2
  3. Novel therapy for locally advanced triple-negative breast cancer vol.47, pp.4, 2015, https://doi.org/10.3892/ijo.2015.3113
  4. combination therapy vol.55, pp.8, 2015, https://doi.org/10.1002/jobm.201400903
  5. Real-time cytometric assay of nitric oxide and superoxide interaction in peripheral blood monocytes: A no-wash, no-lyse kinetic method vol.92, pp.3, 2015, https://doi.org/10.1002/cyto.b.21237
  6. Peroxiredoxin 1 - an antioxidant enzyme in cancer vol.21, pp.1, 2016, https://doi.org/10.1111/jcmm.12955