Activation of β2-adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells.
Activation of β2-adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells.
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DOI：
10.1111/cas.14670
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发表时间：
2021-01
期刊：
影响因子：
5.7
通讯作者：
Watabe T
中科院分区：
文献类型：
--
作者：
Sakakitani S;Podyma-Inoue KA;Takayama R;Takahashi K;Ishigami-Yuasa M;Kagechika H;Harada H;Watabe T
转移是口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）患者死亡的主要原因。一种称为上皮间质转化（EMT）的程序已被证明在促进上皮源性癌转移中起关键作用。在EMT期间，上皮癌细胞获得能动的间充质表型并从原发性肿瘤中分离。最近的证据表明，EMT赋予癌细胞肿瘤起始能力。因此，选择性靶向EMT将导致开发有效的治疗剂。在这项研究中，使用化学生物学方法，我们确定了isoxsuprine，一种β2-肾上腺素能受体（β2-AR）激动剂，作为一种低分子量化合物，干扰口腔癌细胞间充质表型的获得。用异氧舒平治疗多种类型的口腔癌细胞导致间充质细胞标志物下调，伴随着细胞运动性降低。异丙肾上腺素（一种非选择性β-肾上腺素能受体（β-AR）激动剂）也观察到类似的抑制作用。此外，用异氧舒林处理后细胞迁移的抑制被非选择性β-AR拮抗剂普萘洛尔和CRISPR/Cas9系统介导的β2-AR基因缺失逆转，表明异氧舒林产生的作用涉及β2-AR介导的信号。此外，在口腔癌细胞的皮下异种移植模型中，给予异舒丙啶有效地抑制了原发性肿瘤生长，表明β2-AR信号是治疗OSCC的有希望的癌症治疗靶点。在这项研究中，我们确定了异氧舒林，一种β2-肾上腺素能受体激动剂，作为口腔鳞状细胞癌细胞间质表型和迁移的有效抑制剂，这表明β2-肾上腺素能受体信号是治疗口腔癌的一个新的有前途的治疗靶点。
Metastasis is a primary reason related to the mortality of oral squamous cell carcinoma (OSCC) patients. A program called epithelial‐mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium‐derived carcinoma. During EMT, epithelial cancer cells acquire motile mesenchymal phenotypes and detach from primary tumors. Recent lines of evidence have suggested that EMT confers cancer cells with tumor‐initiating ability. Therefore, selective targeting of EMT would lead to the development of effective therapeutic agents. In this study, using a chemical biology approach, we identified isoxsuprine, a β2‐adrenergic receptor (β2‐AR) agonist as a low‐molecular‐weight compound that interferes with the acquisition of mesenchymal phenotypes of oral cancer cells. Treatment of multiple types of oral cancer cells with isoxsuprine led to the downregulation of mesenchymal cell markers that was accompanied by reduced cell motility. Similar inhibitory effects were also observed for isoprenaline, a non‐selective β‐adrenergic receptor (β‐AR) agonist. In addition, inhibition of cell migration upon treatment with isoxsuprine was reverted by a non‐selective β‐AR antagonist, propranolol, and the CRISPR/Cas9 system‐mediated deletion of the β2‐AR gene, suggesting that the effects exerted by isoxsuprine involved signals mediated by β2‐AR. In addition, in a subcutaneous xenograft model of oral cancer cells, the administration of isoxsuprine effectively suppressed primary tumor growth, suggesting β2‐AR signals to be a promising cancer therapeutic target for treatment of OSCC. In this study we identified isoxsuprine, a β2‐adrenergic receptor agonist as an effective inhibitor of mesenchymal phenotypes and migration of oral squamous cell carcinoma cells suggesting that β2‐adrenergic receptor signal is a new promising therapeutic target for treatment of oral cancer.
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