Abstract
Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action. Crizotinib strongly suppressed the growth and proliferation of pancreatic cancer cells in a dose-dependent manner. Also, it induced apoptosis by modulating its related factors. In the study, with regard to the mechanism of action, Crizotinib did not inhibit c-MET expression on pancreatic cancer cells; instead, it specifically inhibited the activity of ALK, which was identified to be highly expressed on various pancreatic cancer cells and tissues in our study. In 42 different receptor tyrosine kinase (RTKs) array, Crizotinib also strongly inhibited the expression of activated ALK in pancreatic cancer cells, modulating its downstream mediators such as STAT3, AKT, and ERK. Furthermore, Crizotinib inhibited angiogenesis in a mouse Matrigel plug assay as well as the progression of tumor growth in a mouse xenograft model. Taken together, our investigation shows that Crizotinib inhibits the ALK signaling pathway in pancreatic cancer, resulting in cell growth/angiogenesis inhibition and apoptosis induction. We suggest that Crizotinib might be used as a novel therapeutic drug for treating pancreatic cancer.
Highlights
Advanced stage pancreatic cancer is the fourth leading cause of cancer-related deaths in the United State [1]
Our present study revealed that Crizotinib induced apoptosis and inhibited cell growth or angiogenesis via inhibition of Anaplastic lymphoma kinase (ALK) signaling, not c-MET signaling in pancreatic cancer
Crizotinib inhibited cell growth and proliferation in pancreatic cancer cells To evaluate the effect of Crizotinib on the growth and proliferation of pancreatic cancer cells (AsPC-1, PANC-1 and MIA PaCa-2), we used MTT assay and BrdU staining
Summary
Advanced stage pancreatic cancer is the fourth leading cause of cancer-related deaths in the United State [1]. Our present study revealed that Crizotinib induced apoptosis and inhibited cell growth or angiogenesis via inhibition of ALK signaling, not c-MET signaling in pancreatic cancer. When pancreatic cancer cells were treated with Crizotinib in a dose-dependent manner, it did not inhibit the expression of both p-c-MET and c-MET (Fig. 3B).
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