文章：

选择性激活M1毒蕈碱受体可抑制人结肠癌细胞增殖

Selective Activation of M1Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation

原文发布日期：28 September 2023

DOI: 10.3390/cancers15194766

类型: Article

开放获取: 是

英文摘要：

M3muscarinic receptor (M3R) activation stimulates colon cancer cell proliferation, migration, and invasion; M3R expression is augmented in colon cancer and ablating M3R expression in mice attenuates colon neoplasia. Several lines of investigation suggest that in contrast to these pro-neoplastic effects of M3R, M1R plays an opposite role, protecting colon epithelial cells against neoplastic transformation. To pursue these intriguing findings, we examined the relative expression of M1R versus M3R in progressive stages of colon neoplasia and the effect of treating colon cancer cells with selective M1R agonists. We detected divergent expression of M1R and M3R in progressive colon neoplasia, from aberrant crypt foci to adenomas, primary colon cancers, and colon cancer metastases. Treating three human colon cancer cell lines with two selective M1R agonists, we found that in contrast to the effects of M3R activation, selective activation of M1R reversibly inhibited cell proliferation. Moreover, these effects were diminished by pre-incubating cells with a selective M1R inhibitor. Mechanistic insights were gained using selective chemical inhibitors of post-muscarinic receptor signaling molecules and immunoblotting to demonstrate M1R-dependent changes in the activation (phosphorylation) of key downstream kinases, EGFR, ERK1/2, and p38 MAPK. We did not detect a role for drug toxicity, cellular senescence, or apoptosis in mediating M1R agonist-induced attenuated cell proliferation. Lastly, adding M1R-selective agonists to colon cancer cells augmented the anti-proliferative effects of conventional chemotherapeutic agents. Collectively, these results suggest that selective M1R agonism for advanced colon cancer, alone or in combination with conventional chemotherapy, is a therapeutic strategy worth exploring.

摘要翻译： 

M3毒蕈碱受体（M3R）的激活可刺激结肠癌细胞增殖、迁移和侵袭；M3R在结肠癌中表达增强，而在小鼠中敲除M3R表达可减轻结肠肿瘤发生。多项研究表明，与M3R的这些促肿瘤作用相反，M1R发挥相反作用，保护结肠上皮细胞免受肿瘤转化。为深入探究这些引人注目的发现，我们检测了结肠肿瘤进展阶段中M1R与M3R的相对表达情况，以及选择性M1R激动剂处理结肠癌细胞的效果。我们发现在从异常隐窝灶到腺瘤、原发性结肠癌及结肠癌转移的渐进性结肠肿瘤进程中，M1R与M3R呈现差异表达。使用两种选择性M1R激动剂处理三种人结肠癌细胞系后，我们发现与M3R激活效应相反，选择性激活M1R可逆地抑制细胞增殖。此外，通过预孵育选择性M1R抑制剂可减弱这些效应。通过使用毒蕈碱受体后信号分子的选择性化学抑制剂及免疫印迹技术，我们揭示了M1R依赖性调控关键下游激酶（EGFR、ERK1/2和p38 MAPK）激活（磷酸化）的分子机制。未发现药物毒性、细胞衰老或凋亡在介导M1R激动剂诱导的细胞增殖抑制中发挥作用。最后，在结肠癌细胞中添加M1R选择性激动剂可增强传统化疗药物的抗增殖效果。综上所述，这些结果表明，针对晚期结肠癌采用选择性M1R激动疗法（单独或联合传统化疗）是值得探索的治疗策略。

原文链接：

Selective Activation of M1Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation