CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field.