Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation
Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation
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乙酰胆碱通过M3毒蕈碱受体激活EGFR信号传导并促进胃癌细胞增殖
DOI：
10.1038/srep40802
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发表时间：
2017-01
影响因子：
4.6
通讯作者：
Bi Feng
中科院分区：
文献类型：
--
作者：
Yu Huangfei;Xia Hongwei;Tang Qiulin;Bi Feng
乙酰胆碱（Acetylcholine，ACh）是一种神经递质，调节中枢和外周神经系统的多种功能。近年来，越来越多的证据表明ACh在肿瘤发生中也起着重要作用。然而，关于ACh在胃癌中的作用知之甚少。本文报道了胃癌细胞MKN 45和BGC 823可自行合成和释放乙酰胆碱。外源性ACh以剂量依赖方式促进细胞增殖。M3受体拮抗剂4-DAMP可逆转ACh诱导的细胞增殖，而M1受体拮抗剂苯海索和M2/4受体拮抗剂AFDX-116则不能。ACh通过M3 R激活EGFR信号通路，诱导ERK 1/2和AKT磷酸化，特异性抑制剂AG 1478阻断EGFR通路可抑制ACh诱导的细胞增殖。此外，M3受体拮抗剂4-DAMP和达非那新可明显抑制胃肿瘤的形成。4-DAMP还能显著增强5-Fu对MKN 45和BGC 823细胞的杀伤活性，并诱导凋亡相关蛋白Bax和Caspase-3的表达。这些结果表明，ACh自分泌可能通过M3 R和EGFR信号通路促进胃癌细胞增殖，靶向M3 R或EGFR可能为胃癌的治疗提供一种潜在的治疗策略。
Acetylcholine (ACh), known as a neurotransmitter, regulates the functions of numerous fundamental central and peripheral nervous system. Recently, emerging evidences indicate that ACh also plays an important role in tumorigenesis. However, little is known about the role of ACh in gastric cancer. Here, we reported that ACh could be auto-synthesized and released from MKN45 and BGC823 gastric cancer cells. Exogenous ACh promoted cell proliferation in a does-dependent manner. The M3R antagonist 4-DAMP, but not M1R antagonist trihexyphenidyl and M2/4 R antagonist AFDX-116, could reverse the ACh-induced cell proliferation. Moreover, ACh, via M3R, activated the EGFR signaling to induce the phosphorylation of ERK1/2 and AKT, and blocking EGFR pathway by specific inhibitor AG1478 suppressed the ACh induced cell proliferation. Furthermore, the M3R antagonist 4-DAMP and darifenacin could markedly inhibit gastric tumor formationin vivo. 4-DAMP could also significantly enhance the cytotoxic activity of 5-Fu against the MKN45 and BGC823 cells, and induce the expression of apoptosis-related proteins such as Bax and Caspase-3. Together, these findings indicated that the autocrine ACh could act through M3R and the EGFR signaling to promote gastric cancer cells proliferation, targeting M3R or EGFR may provide us a potential therapeutic strategy for gastric cancer treatment.
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DOI：
10.1891/9780826121646.0002
发表时间：
2018-09
期刊：
Cancer Rehabilitation
影响因子：
--
作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
通讯作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
影响因子：
--
作者：
Shiozaki H;Shimodaira Y;Elimova E;Wadhwa R;Sudo K;Harada K;Estrella JS;Das P;Badgwell B;Ajani JA
通讯作者：
Ajani JA
影响因子：
3.8
作者：
Castillo-González AC;Nieto-Cerón S;Pelegrín-Hernández JP;Montenegro MF;Noguera JA;López-Moreno MF;Rodríguez-López JN;Vidal CJ;Hellín-Meseguer D;Cabezas-Herrera J
通讯作者：
Cabezas-Herrera J
影响因子：
5.3
作者：
Hall JM;Savage LM
通讯作者：
Savage LM
影响因子：
3.4
作者：
van der Pijl，Elizabeth M.;van Putten，Maaike;Plomp，Jaap J.
通讯作者：
Plomp，Jaap J.