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.
Highlights
Breast cancer is the most common type of malignancy in women and is the second leading cause of female cancer mortality in the world [1,2,3]
We investigated whether nilotinib inhibited the colony formation capability of breast cancer cells, a part of the tumor proliferation process
We found that nilotinib promoted MCF-7 and MDA-MB-231 cells apoptosis via caspase-3 (Figure 1E), nilotinib modulated the level of cleaved caspase-3
Summary
Breast cancer is the most common type of malignancy in women and is the second leading cause of female cancer mortality in the world [1,2,3]. Activation of DDR1 by collagen IV induces the MAPK signaling pathway, promoting the proliferation of malignant breast cancer cells [14, 15]. Nilotinib has been identified as a brand-new method for the treatment of metastatic colorectal cancer by the inhibition of the DDR1-BCR signaling pathway [22, 23] and nilotinib has been reported as an ABL kinase inhibitor for blocking breast cancer metastasis [23]. There are no reports on the evaluation of nilotinib as a novel DDR1 inhibitor for the treatment of breast cancer. Our main aim is to illuminate the biological role of the DDR1 signaling pathway in breast carcinoma and to evaluate the inhibitory activity of nilotinib against breast cancer
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