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 nonobese diabetic-
severe combined immunodeficiency (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
reactive oxygen species (ROS)-dependent
nuclear factor kappa B (NF-κB) 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 and 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-κB-dependent NLRP3
inflammasome activation in BC cells, leading to increase in
inflammation cytokines such as
interleukin (IL)-6,
tumor necrosis factor alpha (TNF-α),
vascular endothelial growth factor (
VEGF), intercellular
cell adhesion molecule 1 (ICAM-1),
vascular cell adhesion molecule 1 (VCAM-1), IL-1β and
IL-33, and MDSCs inductors
granulocyte-macrophage colony-stimulating factor (
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-κB-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.