Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells.
Soonbum ParkEun A ChoJung Nyeo ChunDa Young LeeSanghoon LeeMi Yeon KimSang Mun BaeSu In JoSo Hee LeeHyun Ho ParkTae Min KimInsuk SoSang-Yeob KimJu-Hong JeonPublished in: Experimental & molecular medicine (2022)
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.
Keyphrases
- advanced non small cell lung cancer
- small cell lung cancer
- epidermal growth factor receptor
- induced apoptosis
- transforming growth factor
- cell cycle arrest
- squamous cell carcinoma
- tyrosine kinase
- molecular docking
- single cell
- cell death
- cell therapy
- papillary thyroid
- molecular dynamics simulations
- epithelial mesenchymal transition
- locally advanced
- oxidative stress
- lymph node
- radiation therapy
- rectal cancer
- high throughput
- photodynamic therapy
- mesenchymal stem cells
- bone marrow
- pi k akt
- neoadjuvant chemotherapy
- combination therapy