Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells.
Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells.
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DOI：
10.1038/s12276-022-00835-8
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发表时间：
2022-08
影响因子：
12.8
通讯作者：
Jeon JH
中科院分区：
文献类型：
--
作者：
Park S;Cho EA;Chun JN;Lee DY;Lee S;Kim MY;Bae SM;Jo SI;Lee SH;Park HH;Kim TM;So I;Kim SY;Jeon JH
Crizotinib是一种临床批准的酪氨酸激酶抑制剂，用于治疗EML4-ALK融合的局部晚期或转移性非小细胞肺癌(NSCLC)患者。Crizotinib最初是作为MET(HGF受体)的抑制剂而开发的，MET参与了转移级联反应。然而，关于Crizotinib是否抑制NSCLC细胞中的肿瘤转移，人们知之甚少。在本研究中，我们发现，在非小细胞肺癌细胞中，克里佐替尼通过非依赖于ALK/MET/RON/ROS1的方式阻断Smad的磷酸化，从而抑制转化生长因子β信号转导。分子对接和体外酶活性测定表明，克里佐替尼通过竞争性抑制方式直接抑制转化生长因子β受体I的激酶活性。细胞跟踪、划痕损伤和跨孔迁移分析表明，克里佐替尼同时抑制转化生长因子β和肝细胞生长因子介导的非小细胞肺癌细胞的迁移和侵袭。此外，体内生物发光成像分析表明，克里佐替尼抑制了NSCLC细胞的转移能力。我们的结果表明，克里佐替尼通过抑制非小细胞肺癌细胞中转化生长因子β信号转导来减少肿瘤转移。因此，我们的发现将有助于推进我们对克里佐替尼抗癌作用的理解，并为未来的临床研究提供洞察力。研究一种现有抗癌药物的活性表明，它可以限制非小细胞肺癌(NSCLC)的转移(癌症扩散)。转化生长因子β(转化生长因子β)蛋白信号的异常与非小细胞肺癌的转移密切相关。药物Crizotinib已被临床批准用于非小细胞肺癌，但它是否会影响转移尚不清楚。Ju-hong Jeon(首尔国立大学医学院)、Sang-yeob Kim(首尔峨山医学中心)及其同事使用细胞培养和小鼠模型来研究Crizotinib是否可以抑制转化生长因子β。克里佐替尼通过阻断关键蛋白的磷酸化和抑制转化生长因子β受体的酶活性来抑制转化生长因子β信号转导。这些作用减少了通常由转化生长因子β介导的细胞迁移和侵袭。结果还表明，癌症信号通路可以独立发挥作用，这意味着多靶点方法可能会改善治疗。
Crizotinib is a clinically approved tyrosine kinase inhibitor for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion. Crizotinib was originally developed as an inhibitor of MET (HGF receptor), which is involved in the metastatic cascade. However, little is known about whether crizotinib inhibits tumor metastasis in NSCLC cells. In this study, we found that crizotinib suppressed TGFβ signaling by blocking Smad phosphorylation in an ALK/MET/RON/ROS1-independent manner in NSCLC cells. Molecular docking and in vitro enzyme activity assays showed that crizotinib directly inhibited the kinase activity of TGFβ receptor I through a competitive inhibition mode. Cell tracking, scratch wound, and transwell migration assays showed that crizotinib simultaneously inhibited TGFβ- and HGF-mediated NSCLC cell migration and invasion. In addition, in vivo bioluminescence imaging analysis showed that crizotinib suppressed the metastatic capacity of NSCLC cells. Our results demonstrate that crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in NSCLC cells. Therefore, our findings will help to advance our understanding of the anticancer action of crizotinib and provide insight into future clinical investigations. Investigating the activity of an existing anticancer drug shows that it can limit metastasis (cancer spread) in non-small-cell lung cancer (NSCLC). Aberrant signaling from the transforming growth factor β (TGFβ) protein is known to trigger metastasis in NSCLC. The drug crizotinib is clinically approved for NSCLC, but whether it can affect metastasis is unclear. Ju-Hong Jeon (Seoul National University College of Medicine), Sang-Yeob Kim (ASAN Medical Center, Seoul) and co-workers used cell cultures and a mouse model to examine if crizotinib can inhibit TGFβ. Crizotinib suppressed TGFβ signaling by blocking the phosphorylation of a critical protein and inhibiting the enzymatic activity of a TGFβ receptor. These actions reduced the cell migration and invasion usually mediated by TGFβ. The results also indicate that cancer signaling pathways can act independently, meaning that a multitarget approach may improve treatment.
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