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

Abstract Background: 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. Methods: 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 against MCF-7 and MDA-MB-231. Expression of DDR1 was manipulated in MCF-7 cell lines with low level DDR1 expression by transfecting with plasmids containing by 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 were detected by western blot and immuno-fluorescent staining . Results: Nilotinib against MCF-7 (IC 50 =0.403 μM) and MDA-MB-231 (IC 50 =0.819 μM) and also indicated induced apoptotic cell death after co-cuturing with Nilotinib (500 nM), apoptosis rate is 29.60 % ± 2.19% and 18.75 % ± 2.30% respective ly. Moreover, Nilotinib effectually blocked cellular migration of MCF-7. Interestingly, Knock-down DDR1 could significantly block the migration of breast cancer, meantime the sensitivity of Nilotinib to MCF-7 was reduced. Conclusion: Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and Nilotinib could as a candidate for the treatment of breast cancer.

Download Full-text

Abstract LB-055: Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive, basal-like breast cancer

10.1158/1538-7445.am2018-lb-055 ◽

2018 ◽

Author(s):

Allison P. Drain ◽

Ken Takai ◽

Devon A. Lawson ◽

Laurie E. Littlepage ◽

Marcela Karpuj ◽

...

Keyword(s):

Breast Cancer ◽

Tissue Fibrosis ◽

Discoidin Domain Receptor ◽

Basal Like Breast Cancer ◽

Discoidin Domain Receptor 1

Download Full-text

A Membrane-Type-1 Matrix Metalloproteinase (MT1-MMP) – Discoidin Domain Receptor 1 Axis Regulates Collagen-Induced Apoptosis in Breast Cancer Cells

PLoS ONE ◽

10.1371/journal.pone.0116006 ◽

2015 ◽

Vol 10 (3) ◽

pp. e0116006 ◽

Cited By ~ 22

Author(s):

Delphine Assent ◽

Isabelle Bourgot ◽

Benoît Hennuy ◽

Pierre Geurts ◽

Agnès Noël ◽

...

Keyword(s):

Breast Cancer ◽

Matrix Metalloproteinase ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Discoidin Domain Receptor ◽

Membrane Type ◽

Induced Apoptosis ◽

Discoidin Domain Receptor 1

Download Full-text

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

10.21203/rs.2.15285/v3 ◽

2020 ◽

Author(s):

Shufang Yu ◽

Shuang Wang ◽

Yanping Xie ◽

Aina Bao ◽

Jing Li ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

Cell Death ◽

Apoptotic Cell ◽

Cellular Migration ◽

Fluorescent Staining ◽

Discoidin Domain Receptor ◽

Apoptotic Activity ◽

Discoidin Domain Receptor 1 ◽

Mcf 7

Abstract Background: 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. Methods: 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 against MCF-7 and MDA-MB-231. Expression of DDR1 was manipulated in MCF-7 cell lines with low level DDR1 expression by transfecting with plasmids containing by 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 were detected by western blot and immuno-fluorescent staining . Results: Nilotinib against MCF-7 (IC 50 =0.403 μM) and MDA-MB-231 (IC 50 =0.819 μM) and also indicated induced apoptotic cell death after co-cuturing with Nilotinib (500 nM), apoptosis rate is 29.60 % ± 2.19% and 18.75 % ± 2.30% respective ly. Moreover, Nilotinib effectually blocked cellular migration of MCF-7. Interestingly, Knock-down DDR1 could significantly block the migration of breast cancer, meantime the sensitivity of Nilotinib to MCF-7 was reduced. Conclusion: Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and Nilotinib could as a candidate for the treatment of breast cancer.

Download Full-text

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

10.21203/rs.2.15285/v4 ◽

2020 ◽

Author(s):

Shufang Yu ◽

Shuang Wang ◽

Yanping Xie ◽

Aina Bao ◽

Jing Li ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

Cell Death ◽

Apoptotic Cell ◽

Cellular Migration ◽

Fluorescent Staining ◽

Discoidin Domain Receptor ◽

Apoptotic Activity ◽

Discoidin Domain Receptor 1 ◽

Mcf 7

Abstract Background: 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. Methods: 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 against MCF-7 and MDA-MB-231. Expression of DDR1 was manipulated in MCF-7 cell lines with low level DDR1 expression by transfecting with plasmids containing by 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 were detected by western blot and immuno-fluorescent staining.Results: Nilotinib against MCF-7 (IC50=0.403 μM) and MDA-MB-231 (IC50=0.819 μM) and also indicated induced apoptotic cell death after co-cuturing with Nilotinib (500 nM), apoptosis rate is 29.60 % ± 2.19% and 18.75 % ± 2.30% respectively. Moreover, Nilotinib effectually blocked cellular migration of MCF-7. Interestingly, Knock-down DDR1 could significantly block the migration of breast cancer, meantime the sensitivity of MCF-7 to Nilotinib was reduced.Conclusion: Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and Nilotinib could as a candidate for the treatment of breast cancer.

Download Full-text

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

10.21203/rs.2.15285/v2 ◽

2020 ◽

Author(s):

Shufang Yu ◽

Shuang Wang ◽

Yanping Xie ◽

Aina Bao ◽

Jing Li ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

Cell Death ◽

Apoptotic Cell ◽

Cellular Migration ◽

Fluorescent Staining ◽

Discoidin Domain Receptor ◽

Apoptotic Activity ◽

Discoidin Domain Receptor 1 ◽

Mcf 7

Abstract Background: 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. Methods: 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 against MCF-7 and MDA-MB-231. Expression of DDR1 was manipulated in MCF-7 cell lines with low level DDR1 expression by transfecting with plasmids containing by 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 were detected by western blot and immuno-fluorescent staining . Results: Nilotinib against MCF-7 (IC 50 =0.403 μM) and MDA-MB-231 (IC 50 =0.819 μM) and also indicated induced apoptotic cell death after co-cuturing with Nilotinib (500 nM), apoptosis rate is 29.60 % ± 2.19% and 18.75 % ± 2.30% respective ly. Moreover, Nilotinib effectually blocked cellular migration of MCF-7. Interestingly, Knock-down DDR1 could significantly block the migration of breast cancer, meantime the sensitivity of Nilotinib to MCF-7 was reduced. Conclusion: Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and Nilotinib could as a candidate for the treatment of breast cancer.

Download Full-text

Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-Integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

International Journal of Molecular Sciences ◽

10.3390/ijms21144956 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4956 ◽

Cited By ~ 1

Author(s):

Fabian Baltes ◽

Julia Caspers ◽

Svenja Henze ◽

Martin Schlesinger ◽

Gerd Bendas

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Collagen Type ◽

Mapk Pathway ◽

Extracellular Matrix Protein ◽

Discoidin Domain Receptor ◽

Collagen Type 1 ◽

Discoidin Domain Receptor 1

Collagen type 1 (COL1) is a ubiquitously existing extracellular matrix protein whose high density in breast tissue favors metastasis and chemoresistance. COL1-binding of MDA-MB-231 and MCF-7 breast cancer cells is mainly dependent on β1-integrins (ITGB1). Here, we elucidate the signaling of chemoresistance in both cell lines and their ITGB1-knockdown mutants and elucidated MAPK pathway to be strongly upregulated upon COL1 binding. Notably, Discoidin Domain Receptor 1 (DDR1) was identified as another important COL1-sensor, which is permanently active but takes over the role of COL1-receptor maintaining MAPK activation in ITGB1-knockdown cells. Consequently, inhibition of DDR1 and ERK1/2 act synergistically, and sensitize the cells for cytostatic treatments using mitoxantrone, or doxorubicin, which was associated with an impaired ABCG2 drug efflux transporter activity. These data favor DDR1 as a promising target for cancer cell sensitization, most likely in combination with MAPK pathway inhibitors to circumvent COL1 induced transporter resistance axis. Since ITGB1-knockdown also induces upregulation of pEGFR in MDA-MB-231 cells, inhibitory approaches including EGFR inhibitors, such as gefitinib appear promising for pharmacological interference. These findings provide evidence for the highly dynamic adaptation of breast cancer cells in maintaining matrix binding to circumvent cytotoxicity and highlight DDR1 signaling as a target for sensitization approaches.

Download Full-text