scholarly journals Deficiency in Dipeptidyl Peptidase-4 Promotes Chemoresistance Through the CXCL12/CXCR4/mTOR/TGFβ Signaling Pathway in Breast Cancer Cells

2020 ◽  
Vol 21 (3) ◽  
pp. 805 ◽  
Author(s):  
Shaolan Li ◽  
Yang Fan ◽  
Asako Kumagai ◽  
Emi Kawakita ◽  
Munehiro Kitada ◽  
...  

Dipeptidyl peptidase (DPP)-4, a molecular target of DPP-4 inhibitors, which are type 2 diabetes drugs, is expressed in a variety of cell types, tissues and organs. DPP-4 has been shown to be involved in cancer biology, and we have recently shown that a DPP-4 inhibitor promoted the epithelial mesenchymal transition (EMT) in breast cancer cells. The EMT is known to associate with chemotherapy resistance via the induction of ATP-binding cassette (ABC) transporters in cancer cells. Here, we demonstrated that deficiency in DPP-4 promoted chemotherapy resistance via the CXCL12/CXCR4/mTOR axis, activating the TGFβ signaling pathway via the expression of ABC transporters. DPP-4 inhibition enhanced ABC transporters in vivo and in vitro. Doxorubicin (DOX) further induced ABC transporters in DPP-4-deficient 4T1 cells, and the induction of ABC transporters was suppressed by either the CXCR4 inhibitor AMD3100, the mTOR inhibitor rapamycin or a neutralizing TGFβ (1, 2 and 3) antibody(N-TGFβ). Knockdown of snail, an EMT-inducible transcription factor, suppressed ABC transporter levels in DOX-treated DPP-4-deficient 4T1 cells. In an allograft mouse model, however, the effects of DOX in either primary tumor or metastasis were not statistically different between control and DPP-4-kd 4T1. Taken together, our findings suggest that DPP-4 inhibitors potentiate chemotherapy resistance via the induction of ABC transporters by the CXCL12/CXCR4/mTOR/TGFβ signaling pathway in breast cancer cells.

2021 ◽  
pp. 114081
Author(s):  
Min-Gu Lee ◽  
Yun-Suk Kwon ◽  
Kyung-Soo Nam ◽  
Seo Yeon Kim ◽  
In Hyun Hwang ◽  
...  

2013 ◽  
Vol 220 (3) ◽  
pp. 219-228 ◽  
Author(s):  
Hongzhong Li ◽  
Bing Yang ◽  
Jing Huang ◽  
Tingxiu Xiang ◽  
Xuedong Yin ◽  
...  

2019 ◽  
Vol 20 (22) ◽  
pp. 5581
Author(s):  
Chung-Yih Wang ◽  
Chun-Yuan Chang ◽  
Chun-Yu Wang ◽  
Kaili Liu ◽  
Chia-Yun Kang ◽  
...  

Radiation is a widely used therapeutic method for treating breast cancer. N-dihydrogalactochitosan (GC), a biocompatible immunostimulant, is known to enhance the effects of various treatment modalities in different tumor types. However, whether GC can enhance the radiosensitivity of cancer cells remains to be explored. In this study, triple-negative murine 4T1 breast cancer cells transduced with multi-reporter genes were implanted in immunocompetent Balb/C mice to track, dissect, and identify liver-metastatic 4T1 cells. These cells expressed cancer stem cell (CSC) -related characteristics, including the ability to form spheroids, the expression of the CD44 marker, and the increase of protein stability. We then ex vivo investigated the potential effect of GC on the radiosensitivity of the liver-metastatic 4T1 breast cancer cells and compared the results to those of parental 4T1 cells subjected to the same treatment. The cells were irradiated with increased doses of X-rays with or without GC treatment. Colony formation assays were then performed to determine the survival fractions and radiosensitivity of these cells. We found that GC preferably increased the radiosensitivity of liver-metastatic 4T1 breast cancer cells rather than that of the parental cells. Additionally, the single-cell DNA electrophoresis assay (SCDEA) and γ-H2AX foci assay were performed to assess the level of double-stranded DNA breaks (DSBs). Compared to the parental cells, DNA damage was significantly increased in liver-metastatic 4T1 cells after they were treated with GC plus radiation. Further studies on apoptosis showed that this combination treatment increased the sub-G1 population of cells, but not caspase-3 cleavage, in liver-metastatic breast cancer cells. Taken together, the current data suggest that the synergistic effects of GC and irradiation might be used to enhance the efficacy of radiotherapy in treating metastatic tumors.


Life Sciences ◽  
2020 ◽  
Vol 259 ◽  
pp. 118239 ◽  
Author(s):  
Narges Dastmalchi ◽  
Mohammad Ali Hosseinpourfeizi ◽  
Seyed Mahdi Banan Khojasteh ◽  
Behzad Baradaran ◽  
Reza Safaralizadeh

2019 ◽  
Vol 26 (12) ◽  
pp. 2966
Author(s):  
Pinar Demirel ◽  
Umit Ozorhan ◽  
Bilge Tuna ◽  
Margot Cleary ◽  
Soner Dogan

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