Nilotinib, a Discoidin domain receptor 1 (DDR1) inhibitor, induces apoptosis and inhibits migration in breast cancer

Shuai Wang, Yanping Xie, Aina Bao, Jing Li, Tingting Ye, Chu Yang,  Shufang Yu

Abstract:

Overexpression of discoidin domain receptor 1 (DDR1) is known to enhance the malignancy of breast cancer considerably. This study reports the identification of a potent DDR1 inhibitor, nilotinib, for the treatment of breast cancer. MTT assay was used to evaluate the inhibitory activity of nilotinib and meantime we used flow cytometry to evaluate the pro-apoptotic activity of nilotinib in MCF-7 and MDA-MB-231 cells. Expression of DDR1 was manipulated in MDA-MB-231 and MCF-7 cell lines with low-level DDR1 expression by transfecting with plasmids containing shRNA. The effect of DDR1 or treatment with nilotinib on cell migration was assayed. The expression of p-DDR1, DDR1, p-ERK1/2, ERK1/2 and E-cadherin, Vimentin, Snail1, and caspase 3 were detected by western blot and immunofluorescent staining. Nilotinib in MCF-7 (IC50=0.403 μM) and MDA-MB-231 (IC50=0.819 μM) also indicated induced apoptotic cell death. After co-culturing with nilotinib (500 nM), apoptosis rate is 29.60±2.19% and 18.75±2.30%, respectively. Moreover, nilotinib effectually blocked the cellular migration of MCF-7 cells. Interestingly, the knock-down DDR1 could significantly block the migration of breast cancer, while the sensitivity of MCF-7 and MDA-MB-231 cells to nilotinib was reduced. Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and nilotinib could be used as a candidate for the treatment of breast cancer.