Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial-Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-02, Vol.79 (4), p.735-746
• Main Authors: Yang, Fan, Takagaki, Yuta, Yoshitomi, Yasuo, Ikeda, Takayuki, Li, Jinpeng, Kitada, Munehiro, Kumagai, Asako, Kawakita, Emi, Shi, Sen, Kanasaki, Keizo, Koya, Daisuke
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers, Tumor; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Movement; Cell Proliferation; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Dipeptidyl Peptidase 4 - chemistry; Enzyme Inhibitors - pharmacology; Epithelial-Mesenchymal Transition - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Mice; Mice, Inbred BALB C; Mice, Nude; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-0620

Dipeptidyl peptidase (DPP)-4 is a multifunctional glycoprotein involved in various biological and pathologic processes. DPP-4 has been widely recognized as a therapeutic target for type 2 diabetes mellitus but is also implicated in the development of human malignancies. Here, we show that inhibition of DPP-4 accelerates breast cancer metastasis via induction of CXCL12/CXCR4, which activates mTOR to promote epithelial-mesenchymal transition (EMT). In cultured cells, DPP-4 knockdown induced EMT and cell migration. Treatment with the DPP-4 inhibitor KR62436 (KR) promoted primary tumor growth and lung metastasis in a 4T1 tumor allograft mouse model; DPP-4 knockdown in 4T1 cells displayed similar phenotypes and . KR treatment enhanced the levels of CXCL12/CXCR4 and phosphorylated mTOR, which were associated with the induction of EMT in metastatic cancer cells. KR-induced EMT in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 or the mTOR inhibitor rapamycin, and AMD3100 suppressed KR-induced metastasis . Our findings suggest that DPP-4 plays a significant role in cancer biology and that inhibition of DPP-4 promotes cancer metastasis via induction of the CXCL12/CXCR4/mTOR/EMT axis. SIGNIFICANCE: These findings reveal that inhibition of DPP-4 increases the metastatic potential of breast cancer. This is especially important given the potential use of DPP-4 inhibition as a therapeutic strategy for type 2 diabetes.