Antidiabetic DPP-4 Inhibitors Reprogram Tumor Microenvironment That Facilitates Murine Breast Cancer Metastasis Through Interaction With Cancer Cells via a ROS–NF-кB–NLRP3 Axis

Improvement of understanding of the safety profile and biological significance of antidiabetic agents in breast cancer (BC) progression may shed new light on minimizing the unexpected side-effect of antidiabetic reagents in diabetic patients with BC. Our recent finding showed that Saxagliptin (Sax) and Sitagliptin (Sit), two common antidiabetic Dipeptidyl peptidase-4 inhibitors (DPP-4i) compounds, promoted murine BC 4T1 metastasis via a ROS-NRF2-HO-1 axis in NOD-SCID mice. However, the potential role of DPP-4i in BC progression under immune-competent status remains largely unknown. Herein, we extended our investigation and revealed that Sax and Sit also accelerated murine BC 4T1 metastasis in orthotopic, syngeneic and immune-competent BALB/c mice. Mechanically, we found that DPP-4i not only activated ROS-NRF2-HO-1 axis, but also triggered ROS-dependent NF-кB activation and its downstream metastasis-associated gene levels in vitro and in vivo, while NF-кB inhibition significantly abrogated DPP-4i-driven BC metastasis in vitro. Meanwhile, inhibition of NRF2-HO-1 activation attenuated DPP-4i-driven NF-кB activation while NRF2 activator ALA enhanced NF-кB activation, indicating an essential role of ROS-NRF2-HO-1 axis in DPP-4i-driven NF-кB activation. Furthermore, we also found that DPP-4i increased tumor-infiltrating CD45, MPO, F4/80, CD4 and Foxp3-positive cells as well as myeloid-derived suppressor cells (MDSCs), and decreased CD8-positive lymphocytes in metastatic sites, but did not significantly alter cell viability, apoptosis, differentiation and suppressive activation of 4T1-induced splenic MDSCs. Moreover, we revealed that DPP-4i triggered ROS-NF-kB-dependent NLRP3 inflammasome activation in BC cells, leading to increase of inflammation cytokines such as IL-6, TNF-α, VEGF, ICVM-1, VCAM-1, IL-1β and IL-33, as well as MDSCs inductors GM-CSF, G-CSF, and M-CSF, which play a crucial role in the remodeling of tumor immune-suppressive microenvironment. Thus, our findings suggest that antidiabetic DPP-4i reprograms tumor microenvironment that facilitates murine BC metastasis by interaction with BC cells via a ROS-NRF2-HO-1-NF-kB-NLRP3 axis. This finding not only provides a mechanistic insight into the oncogenic ROS-NRF2-HO-1 in DPP-4i-driven BC progression, but also offers novel insights relevant for the improvement of tumor microenvironment to alleviate DPP-4i-induced BC metastasis.