Berberine-induced anticancer activities in FaDu head and neck squamous cell carcinoma cells

Seo,Yo-Seob; Yim,Min-Ji; Kim,Bok-Hee; Kang,Kyung-Rok; Lee,Sook-Young; Oh,Ji-Su; You,Jae-Seek; Kim,Su-Gwan; Yu,Sang-Joun; Lee,Gyeong-Je; Kim,Do  Kyung; Kim,Chun  Sung; Kim,Jin-Soo; Kim,Jae-Sung

doi:10.3892/or.2015.4312

Berberine-induced anticancer activities in FaDu head and neck squamous cell carcinoma cells

Authors:
- Yo-Seob Seo
- Min-Ji Yim
- Bok-Hee Kim
- Kyung-Rok Kang
- Sook-Young Lee
- Ji-Su Oh
- Jae-Seek You
- Su-Gwan Kim
- Sang-Joun Yu
- Gyeong-Je Lee
- Do Kyung Kim
- Chun Sung Kim
- Jin-Soo Kim
- Jae-Sung Kim
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Affiliations: Department of Oral and Maxillofacial Radiology, School of Dentistry, Chosun University, Gwang-Ju 501-759, Republic of Korea, Regional Innovation Center for Dental Science and Engineering, School of Dentistry, Chosun University, Gwang-Ju 501-759, Republic of Korea, Department of Oral and Maxillofacial Surgery, School of Dentistry, Chosun University, Gwang-Ju 501-759, Republic of Korea, Department of Periodontology, School of Dentistry, Chosun University, Gwang-Ju 501-759, Republic of Korea, Department of Prosthodontics, School of Dentistry, Chosun University, Gwang-Ju 501-759, Republic of Korea, Oral Biology Research Institute, School of Dentistry, Chosun University, Gwang-Ju 501-759, Republic of Korea, Pre-Dentistry, School of Dentistry, Chosun University, Gwang-Ju 501-759, Republic of Korea
Published online on: September 25, 2015 https://doi.org/10.3892/or.2015.4312
Pages: 3025-3034

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Abstract

In the present study, we investigated berberine-induced apoptosis and the signaling pathways underlying its activity in FaDu head and neck squamous cell carcinoma cells. Berberine did not affect the viability of primary human normal oral keratinocytes. In contrast, the cytotoxicity of berberine was significantly increased in FaDu cells stimulated with berberine for 24 h. Furthermore, berberine increased nuclear condensation and apoptosis rates in FaDu cells than those in untreated control cells. Berberine also induced the upregulation of apoptotic ligands, such as FasL and TNF-related apoptosis-inducing ligand, and triggered the activation of caspase-8, -7 and -3, and poly(ADP ribose) polymerase, characteristic of death receptor-dependent extrinsic apoptosis. Moreover, berberine activated the mitochondria‑dependent apoptotic signaling pathway by upregulating pro-apoptotic factors, such as Bax, Bad, Apaf-1, and the active form of caspase-9, and downregulating anti-apoptotic factors, such as Bcl-2 and Bcl-xL. In addition, berberine increased the expression of the tumor suppressor p53 in FaDu cells. The pan-caspase inhibitor Z-VAD-fmk suppressed the activation of caspase-3 and prevented cytotoxicity in FaDu cells treated with berberine. Interestingly, berberine suppressed cell migration through downregulation of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, and MMP-9. Moreover, the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and p38, components of the mitogen-activated protein kinase pathway that are associated with the expression of MMP and VEGF, was suppressed in FaDu cells treated with berberine for 24 h. Therefore, these data suggested that berberine exerted anticancer effects in FaDu cells through induction of apoptosis and suppression of migration. Berberine may have potential applications as a chemotherapeutic agent for the management of head and neck squamous carcinoma.

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1	Sturgis EM and Miller RH: Second primary malignancies in the head and neck cancer patient. Ann Otol Rhinol Laryngol. 104:946–954. 1995. View Article : Google Scholar : PubMed/NCBI
2	Rothman KJ: The effect of alcohol consumption on risk of cancer of the head and neck. Laryngoscope. 88(Suppl 8): 51–55. 1978.PubMed/NCBI
3	Maier H, Dietz A, Gewelke U, Heller WD and Weidauer H: Tobacco and alcohol and the risk of head and neck cancer. Clin Investig. 70:320–327. 1992.PubMed/NCBI
4	Rothman KJ: Epidemiology of head and neck cancer. Laryngoscope. 88:435–438. 1978. View Article : Google Scholar : PubMed/NCBI
5	Lin YS, Jen YM, Wang BB, Lee JC and Kang BH: Epidemiology of oral cavity cancer in Taiwan with emphasis on the role of betel nut chewing. ORL J Otorhinolaryngol Relat Spec. 67:230–236. 2005. View Article : Google Scholar : PubMed/NCBI
6	Mannarini L, Kratochvil V, Calabrese L, Gomes Silva L, Morbini P, Betka J and Benazzo M: Human papilloma virus (HPV) in head and neck region: Review of literature. Acta Otorhinolaryngol Ital. 29:119–126. 2009.
7	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
8	Lacko M, Braakhuis BJ, Sturgis EM, Boedeker CC, Suárez C, Rinaldo A, Ferlito A and Takes RP: Genetic susceptibility to head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 89:38–48. 2014. View Article : Google Scholar : PubMed/NCBI
9	Park MR, Kim SG, Cho IA, Oh D, Kang KR, Lee SY, Moon SM, Cho SS, Yoon G, Kim CS, et al: Licochalcone-A induces intrinsic and extrinsic apoptosis via ERK1/2 and p38 phosphorylation-mediated TRAIL expression in head and neck squamous carcinoma FaDu cells. Food Chem Toxicol. 77:34–43. 2015. View Article : Google Scholar : PubMed/NCBI
10	Fesik SW: Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer. 5:876–885. 2005. View Article : Google Scholar : PubMed/NCBI
11	Renehan AG, Booth C and Potten CS: What is apoptosis, and why is it important? BMJ. 322:1536–1538. 2001. View Article : Google Scholar : PubMed/NCBI
12	Khan KH, Blanco-Codesido M and Molife LR: Cancer therapeutics: Targeting the apoptotic pathway. Crit Rev Oncol Hematol. 90:200–219. 2014. View Article : Google Scholar : PubMed/NCBI
13	Luqmani YA: Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract. 14(Suppl 1): 35–48. 2005. View Article : Google Scholar : PubMed/NCBI
14	Ni WJ, Ding HH and Tang LQ: Berberine as a promising anti-diabetic nephropathy drug: An analysis of its effects and mechanisms. Eur J Pharmacol. 760:103–112. 2015. View Article : Google Scholar : PubMed/NCBI
15	Hu Z, Jiao Q, Ding J, Liu F, Liu R, Shan L, Zeng H, Zhang J and Zhang W: Berberine induces dendritic cell apoptosis and has therapeutic potential for rheumatoid arthritis. Arthritis Rheum. 63:949–959. 2011. View Article : Google Scholar
16	Xiao HB, Sun ZL, Zhang HB and Zhang DS: Berberine inhibits dyslipidemia in C57BL/6 mice with lipopolysaccharide induced inflammation. Pharmacol Rep. 64:889–895. 2012. View Article : Google Scholar : PubMed/NCBI
17	Li Z, Geng YN, Jiang JD and Kong WJ: Antioxidant and anti-in flammatory activities of berberine in the treatment of diabetes mellitus. Evid Based Complement Alternat Med. 2014:2892642014. View Article : Google Scholar
18	Tan Y, Tang Q, Hu BR and Xiang JZ: Antioxidant properties of berberine on cultured rabbit corpus cavernosum smooth muscle cells injured by hydrogen peroxide. Acta Pharmacol Sin. 28:1914–1918. 2007. View Article : Google Scholar : PubMed/NCBI
19	Zhang X, Zhao Y, Zhang M, Pang X, Xu J, Kang C, Li M, Zhang C, Zhang Z, Zhang Y, et al: Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS One. 7:e425292012. View Article : Google Scholar : PubMed/NCBI
20	Kim S, Choi JH, Kim JB, Nam SJ, Yang JH, Kim JH and Lee JE: Berberine suppresses TNF-alpha-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells. Molecules. 13:2975–2985. 2008. View Article : Google Scholar : PubMed/NCBI
21	Li J, Cao B, Liu X, Fu X, Xiong Z, Chen L, Sartor O, Dong Y and Zhang H: Berberine suppresses androgen receptor signaling in prostate cancer. Mol Cancer Ther. 10:1346–1356. 2011. View Article : Google Scholar : PubMed/NCBI
22	Lin JP, Yang JS, Chang NW, Chiu TH, Su CC, Lu KW, Ho YT, Yeh CC, Mei-Dueyang, Lin HJ, et al: GADD153 mediates berberine-induced apoptosis in human cervical cancer Ca ski cells. Anticancer Res. 27:3379–3386. 2007.PubMed/NCBI
23	Lin JP, Yang JS, Wu CC, Lin SS, Hsieh WT, Lin ML, Yu FS, Yu CS, Chen GW, Chang YH, et al: Berberine induced down-regulation of matrix metalloproteinase-1, -2 and -9 in human gastric cancer cells (SNU-5) in vitro. In Vivo. 22:223–230. 2008.PubMed/NCBI
24	Kim JS, Oh D, Yim MJ, Park JJ, Kang KR, Cho IA, Moon SM, Oh JS, You JS, Kim CS, et al: Berberine induces FasL-related apoptosis through p38 activation in KB human oral cancer cells. Oncol Rep. 33:1775–1782. 2015.PubMed/NCBI
25	Kuo CL, Chi CW and Liu TY: Modulation of apoptosis by berberine through inhibition of cyclooxygenase-2 and Mcl-1 expression in oral cancer cells. In Vivo. 19:247–252. 2005.PubMed/NCBI
26	Jin P, Zhang C and Li N: Berberine exhibits antitumor effects in human ovarian cancer cells. Anticancer Agents Med Chem. 15:511–516. 2015. View Article : Google Scholar
27	Kim JS, Ellman MB, An HS, Yan D, van Wijnen AJ, Murphy G, Hoskin DW and Im HJ: Lactoferricin mediates anabolic and anti-catabolic effects in the intervertebral disc. J Cell Physiol. 227:1512–1520. 2012. View Article : Google Scholar
28	Warnakulasuriya S: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 45:309–316. 2009. View Article : Google Scholar
29	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
30	Silverman S Jr: Oral cancer: Complications of therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 88:122–126. 1999. View Article : Google Scholar : PubMed/NCBI
31	Letasiová S, Jantová S, Cipák L and Múcková M: Berberine-anti-proliferative activity in vitro and induction of apoptosis/necrosis of the U937 and B16 cells. Cancer Lett. 239:254–262. 2006. View Article : Google Scholar
32	Oberhammer FA, Hochegger K, Fröschl G, Tiefenbacher R and Pavelka M: Chromatin condensation during apoptosis is accompanied by degradation of lamin A+B, without enhanced activation of cdc2 kinase. J Cell Biol. 126:827–837. 1994. View Article : Google Scholar : PubMed/NCBI
33	Hensley P, Mishra M and Kyprianou N: Targeting caspases in cancer therapeutics. Biol Chem. 394:831–843. 2013. View Article : Google Scholar : PubMed/NCBI
34	Ikner A and Ashkenazi A: TWEAK induces apoptosis through a death-signaling complex comprising receptor-interacting protein 1 (RIP1), Fas-associated death domain (FADD), and caspase-8. J Biol Chem. 286:21546–21554. 2011. View Article : Google Scholar : PubMed/NCBI
35	Li H, Zhu H, Xu CJ and Yuan J: Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 94:491–501. 1998. View Article : Google Scholar : PubMed/NCBI
36	Fischer B, Coelho D, Dufour P, Bergerat JP, Denis JM, Gueulette J and Bischoff P: Caspase 8-mediated cleavage of the pro-apoptotic BCL-2 family member BID in p53-dependent apoptosis. Biochem Biophys Res Commun. 306:516–522. 2003. View Article : Google Scholar : PubMed/NCBI
37	Zhu J, Xiong L, Yu B and Wu J: Apoptosis induced by a new member of saponin family is mediated through caspase-8-dependent cleavage of Bcl-2. Mol Pharmacol. 68:1831–1838. 2005.PubMed/NCBI
38	Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ: The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 75:805–816. 1993. View Article : Google Scholar : PubMed/NCBI
39	Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M and Green DR: Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 303:1010–1014. 2004. View Article : Google Scholar : PubMed/NCBI
40	Wang P, Yu J and Zhang L: The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damage. Proc Natl Acad Sci USA. 104:4054–4059. 2007. View Article : Google Scholar : PubMed/NCBI
41	Wang N, Zhu M, Wang X, Tan HY, Tsao SW and Feng Y: Berberine-induced tumor suppressor p53 up-regulation gets involved in the regulatory network of miR-23a in hepatocellular carcinoma. Biochim Biophys Acta. 1839:849–857. 2014. View Article : Google Scholar : PubMed/NCBI
42	Wang Y, Liu Q, Liu Z, Li B, Sun Z, Zhou H, Zhang X, Gong Y and Shao C: Berberine, a genotoxic alkaloid, induces ATM-Chk1 mediated G2 arrest in prostate cancer cells. Mutat Res. 734:20–29. 2012. View Article : Google Scholar : PubMed/NCBI
43	Wu JX, Zhang DG, Zheng JN and Pei DS: Rap2a is a novel target gene of p53 and regulates cancer cell migration and invasion. Cell Signal. 27:1198–1207. 2015. View Article : Google Scholar : PubMed/NCBI
44	Boudreau HE, Casterline BW, Burke DJ and Leto TL: Wild-type and mutant p53 differentially regulate NADPH oxidase 4 in TGF-β-mediated migration of human lung and breast epithelial cells. Br J Cancer. 110:2569–2582. 2014. View Article : Google Scholar : PubMed/NCBI
45	Momota H, Narita Y, Matsushita Y, Miyakita Y and Shibui S: p53 abnormality and tumor invasion in patients with malignant astrocytoma. Brain Tumor Pathol. 27:95–101. 2010. View Article : Google Scholar : PubMed/NCBI
46	Muller PA, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S, Lukashchuk N, Gillespie DA, Ludwig RL, Gosselin P, et al: Mutant p53 drives invasion by promoting integrin recycling. Cell. 139:1327–1341. 2009. View Article : Google Scholar
47	Chambers AF and Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst. 89:1260–1270. 1997. View Article : Google Scholar : PubMed/NCBI
48	Tomao F, Papa A, Rossi L, Zaccarelli E, Caruso D, Zoratto F, Benedetti Panici P and Tomao S: Angiogenesis and anti-angiogenic agents in cervical cancer. Onco Targets Ther. 7:2237–2248. 2014. View Article : Google Scholar
49	Mukhopadhyay D, Tsiokas L and Sukhatme VP: Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 55:6161–6165. 1995.PubMed/NCBI
50	Qin G, Kishore R, Dolan CM, Silver M, Wecker A, Luedemann CN, Thorne T, Hanley A, Curry C, Heyd L, et al: Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF. Proc Natl Acad Sci USA. 103:11015–11020. 2006. View Article : Google Scholar : PubMed/NCBI
51	Ehrenfeld P, Conejeros I, Pavicic MF, Matus CE, Gonzalez CB, Quest AF, Bhoola KD, Poblete MT, Burgos RA and Figueroa CD: Activation of kinin B1 receptor increases the release of metalloproteases-2 and -9 from both estrogen-sensitive and -insensitive breast cancer cells. Cancer Lett. 301:106–118. 2011. View Article : Google Scholar
52	Eberhardt W, Huwiler A, Beck KF, Walpen S and Pfeilschifter J: Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. J Immunol. 165:5788–5797. 2000. View Article : Google Scholar : PubMed/NCBI
53	Im NK, Jang WJ, Jeong CH and Jeong GS: Delphinidin suppresses PMA-induced MMP-9 expression by blocking the NF-κB activation through MAPK signaling pathways in MCF-7 human breast carcinoma cells. J Med Food. 17:855–861. 2014. View Article : Google Scholar : PubMed/NCBI
54	Lin FY, Hsieh YH, Yang SF, Chen CT, Tang CH, Chou MY, Chuang YT, Lin CW and Chen MK: Resveratrol suppresses TPA-induced matrix metalloproteinase-9 expression through the inhibition of MAPK pathways in oral cancer cells. J Oral Pathol Med. Nov 17–2014.Epub ahead of print. PubMed/NCBI
55	Tong Q, Qing Y, Wu Y, Hu X, Jiang L and Wu X: Dioscin inhibits colon tumor growth and tumor angiogenesis through regulating VEGFR2 and AKT/MAPK signaling pathways. Toxicol Appl Pharmacol. 281:166–173. 2014. View Article : Google Scholar : PubMed/NCBI
56	Wang W, Ren F, Wu Q, Jiang D, Li H and Shi H: MicroRNA-497 suppresses angiogenesis by targeting vascular endothelial growth factor A through the PI3K/AKT and MAPK/ERK pathways in ovarian cancer. Oncol Rep. 32:2127–2133. 2014.PubMed/NCBI