Betel quid extract promotes oral cancer cell migration by activating a muscarinic M4 receptor-mediated signaling cascade involving SFKs and ERK1/2

被引:16
作者
Chiu, Chien-Chih [1 ]
Chen, Bing-Hung [1 ]
Hour, Tzyh-Chyuan [2 ]
Chiang, Wei-Fan [3 ,4 ]
Wu, Yu-Jen [5 ]
Chen, Ching-Yi [1 ]
Chen, Hau-Ren [6 ,7 ]
Chan, Po-Ting [8 ]
Liu, Shyun-Yeu [9 ]
Chen, Jeff Yi-Fu [1 ]
机构
[1] Kaohsiung Med Univ, Dept Biotechnol, Kaohsiung, Taiwan
[2] Kaohsiung Med Univ, Dept Biochem, Kaohsiung, Taiwan
[3] Chi Mei Med Ctr, Dept Oral & Maxillofacial Surg, Liouying, Taiwan
[4] Natl Yang Ming Univ, Sch Dent, Taipei 112, Taiwan
[5] Meiho Inst Technol, Dept Beauty Sci, Pingtung, Taiwan
[6] Natl Chung Cheng Univ, Dept Life Sci, Chiayi, Taiwan
[7] Natl Chung Cheng Univ, Inst Mol Biol, Chiayi, Taiwan
[8] Natl Taiwan Univ, Inst Mol & Cellular Biol, Taipei 10764, Taiwan
[9] Chi Mei Med Ctr, Dept Oral & Maxillofacial Surg, Yongkang, Taiwan
关键词
Betel quid; Oral cancer cell migration; Muscarinic M4 receptor; SFKs; ERK1/2; PROTEIN-COUPLED RECEPTORS; ACETYLCHOLINE-RECEPTORS; ALCOHOL-CONSUMPTION; LUNG-CARCINOMA; CHEWING AREA; SURVIVAL; CAVITY; SMOKING; PHOSPHORYLATION; CARCINOGENESIS;
D O I
10.1016/j.bbrc.2010.07.042
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Betel quid (BQ) is a widely accepted etiological factor for oral squamous cell carcinoma (OSCC) in Southeast Asia, but how BQ chewing leads to oral carcinogenesis remains to be elucidated. We have previously demonstrated that the activation of Src family kinases (SFKs) is critical for BQ-induced oral cancer cell motility. Here we investigate whether this biological effect is mediated by specific membrane receptors in oral cancer cells. We found that BQ-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and cell migration could be inhibited by atropine, suggesting the involvement of the muscarinic receptor family. The enhanced activities of ERK1/2 and cell migration were significantly counteracted by PD102807, the selective antagonist of muscarinic M4 receptor. Moreover, cold BQ extract effectively competed with a known ligand, [H-3]-N-methyl scopolamine, for binding to muscarinic M4 receptor in vitro, thereby implying that BQ could activate motility-promoting signaling pathways through direct interaction with the receptor. The requirement of muscarinic M4 receptor for BQ-induced oral cancer cell migration was demonstrated by knockdown of the receptor using RNA interference (RNAi). Remarkably, ectopic expression of muscarinic M4 receptor in two oral cancer cell lines, Ca9-22 and SCC-9, further augmented BQ-induced cell migration by 83% and 99%, respectively. Finally, we verified that BQ-induced oral cancer cell migration was mediated through a muscarinic M4 receptor --> SFKs --> ERK1/2 signaling pathway. Thus, our findings have identified a novel signaling cascade mediating BQ-induced oral cancer cell motility, which could be a therapeutic target for BQ-related oral malignancies. (C) 2010 Elsevier Inc. All lights reserved.
引用
收藏
页码:60 / 65
页数:6
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