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

Abstract

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.

Sodium-Glucose Co-Transporter 2 Inhibitors May Change the Development of Urinary Tract and Hematological Malignancies as Compared With Dipeptidyl Peptidase-4 Inhibitors: Data of the Post-Hoc Analysis of a Nationwide Study

“…As one of these pathways, DPP-4 inhibition may alter chemokine signaling (e.g., that of CXCL-12 and its downstream receptor CXCR4). This may in turn change the activity of the mammalian target of rapamycin (mTOR) pathway, which could theoretically result in tumor cell proliferation and metastasis formation (15). Some ex vivo data indeed suggest that potential targets of DPP-4/ CD26 could interfere with chemokine signaling, and the expression of DPP-4/CD26 seems to be associated with cancer aggressiveness and outcomes, although data may be controversial concerning whether it may promote or inhibit cancer growth (15).…”

“…This may in turn change the activity of the mammalian target of rapamycin (mTOR) pathway, which could theoretically result in tumor cell proliferation and metastasis formation (15). Some ex vivo data indeed suggest that potential targets of DPP-4/ CD26 could interfere with chemokine signaling, and the expression of DPP-4/CD26 seems to be associated with cancer aggressiveness and outcomes, although data may be controversial concerning whether it may promote or inhibit cancer growth (15). In a mouse model of breast cancer, inhibition of DPP-4 promoted metastasis formation, while metformin had an inhibitory effect on it by influencing mTOR-related signals (16).…”

DPP4 Regulates DHCR24-Mediated Cholesterol Biosynthesis to Promote Methotrexate Resistance in Gestational Trophoblastic Neoplastic Cells

“…Metabolic reprogramming is a hallmark of both diabetes and cancer, which is presented with similar abnormalities in glucose, fatty acid, and cholesterol metabolisms ( 46 ). DPP4 has been identified as a potential regulator that links enhanced cancer risk with metabolic diseases such as hyperglycemia and obesity ( 47 ). DPP4 inhibitors, such as sitagliptin, linagliptin, vildagliptin, and saxagliptin, have good efficacy, safety and tolerability in the treatment of type II diabetes ( 48 ).…”

Potential Effect of DPP-4 Inhibitors Towards Hepatic Diseases and Associated Glucose Intolerance

“…The results suggested for further mechanistic studies into the relationship between DPP-4 inhibitors and cancer biology, particularly in diabetic situations, are an important study subject in both diabetes and oncology. 167 Zhao et al 2017 worked on a meta-analysis of randomized clinical trials on DPP-4 inhibitors and cancer risk in patients with type 2 diabetes and there were 72 studies in all, with 35,768 and 33,319 patients recruited in the DPP-4 inhibitors and comparator medicine trials, respectively. In comparison to the usage of other active medicines or placebo, no significant connections between DPP-4 inhibitor use and cancer development were found.…”