Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins

被引:99
作者
Chen, Ching-Shyang [2 ,3 ,4 ]
Lee, Chia-Hwa [5 ]
Hsieh, Chang-Da [5 ]
Ho, Chi-Tang [6 ]
Pan, Min-Hsiung [7 ]
Huang, Ching-Shui [2 ,3 ,4 ,8 ]
Tu, Shih-Hsin [2 ,3 ,4 ,8 ]
Wang, Ying-Jan [9 ]
Chen, Li-Ching [5 ]
Chang, Yu-Jia [2 ,3 ,4 ,11 ,12 ]
Wei, Po-Li [2 ,3 ,4 ,11 ]
Yang, Yi-Yuan [1 ,2 ,3 ,4 ]
Wu, Chih-Hsiung [10 ,11 ]
Ho, Yuan-Soon [1 ,5 ,11 ]
机构
[1] Taipei Med Univ, Grad Inst Biomed Technol, Taipei 110, Taiwan
[2] Taipei Med Univ, Dept Surg, Taipei 110, Taiwan
[3] Taipei Med Univ, Ctr Qual Management, Taipei 110, Taiwan
[4] Taipei Med Univ, Breast Hlth Ctr, Taipei 110, Taiwan
[5] Taipei Med Univ, Grad Inst Med Sci, Taipei 110, Taiwan
[6] Rutgers State Univ, Dept Food Sci, New Brunswick, NJ 08903 USA
[7] Natl Kaohsiung Marine Univ, Dept Seafood Sci, Kaohsiung, Taiwan
[8] Cathay Gen Hosp, Dept Surg, Taipei, Taiwan
[9] Natl Cheng Kung Univ, Coll Med, Dept Environm & Occupat Hlth, Tainan 70101, Taiwan
[10] Taipei Med Univ, Shuang Ho Hosp, Sch Med, Dept Surg, Jhonghe City, Taipei County, Taiwan
[11] Taipei Med Univ, Ctr Excellence Canc Res, Taipei 110, Taiwan
[12] Taipei Med Univ, Grad Inst Clin Med, Taipei 110, Taiwan
关键词
Smoking; Cyclin D3; Garcinol; Nicotinic acetylcholine receptors; Breast cancer; ALPHA-9; ACETYLCHOLINE-RECEPTOR; MEDIATED TOBACCO TOXICITY; EPITHELIAL-CELLS; KERATINOCYTE ADHESION; PASSIVE SMOKING; GROWTH-FACTOR; UP-REGULATION; CYTOCHROME-C; EXPRESSION; D1;
D O I
10.1007/s10549-010-0821-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Previous studies have demonstrated that the persistent exposure of human bronchial epithelial cells to nicotine (Nic) through nicotinic acetylcholine receptors increases cyclin D1 promoter activity and protein expression. The main purpose of this study is to elucidate the carcinogenic role of cyclin D3, which is involved in breast tumorigenesis when induced by Nic. Real-time PCR analysis revealed that cyclin D3 is highly expressed at the mRNA level in surgically dissected breast tumor tissue, compared to the surrounding normal tissue (tumor/normal fold ratio = 17.93, n = 74). To test whether Nic/nicotinic acetylcholine receptor (nAChR) binding could affect cyclin D3 expression in human breast cancer cells, the transformed cell line MCF-10A-Nic (DOX) was generated from normal breast epithelial cells (MCF-10A) with inducible alpha 9-nAChR gene expression, using the adenovirus tetracycline-regulated Tet-off system. Tet-regulated overexpression of alpha 9-nAChR in MCF-10A-Nic (DOX) xenografted BALB/c-nu/nu mice resulted in a significant induction of cyclin D3. In contrast, cyclin D3 expression was down-regulated in alpha 9-nAChR knock-down (siRNA) MDA-MB-231-xenografted tumors in NOD.CB17-PRKDC(SCID)/J(NOD-SCID) mice. Furthermore, we found that Nic-induced human breast cancer (MDA-MB-231) cell proliferation was inhibited by 1 mu M of garcinol (Gar), isolated from the edible fruit Garcinia indica, through down-regulation of alpha 9-nAChR and cyclin D3 expression. These results suggest that alpha 9-nAChR-mediated cyclin D3 overexpression is important for nicotine-induced transformation of normal human breast epithelial cells. The homeostatic regulation of cyclin D3 has the potential to be a molecular target for antitumor chemotherapeutic or chemopreventive purposes in clinical breast cancer patients.
引用
收藏
页码:73 / 87
页数:15
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