sitagliptin-phosphate and Carcinoma

Dipeptidyl peptidase IV (DPP4) is overexpressed in thyroid cancer and certain malignancies. Furthermore, DPP4 has been identified as a discriminatory marker for thyroid cancer. However, it remains unclear whether DPP4 expression plays a prognostic role.. The aim of this study was to investigate the expression and function of DPP4 in thyroid cancer and the mechanisms involved.. We determined the expression of DPP4 by immunohistochemistry in tissue microarrays of thyroid tumors. In vitro functional studies were performed after genetic and pharmacological inhibition of DPP4. Gene expression and pathway analyses were used to identify downstream targets. The therapeutic potential of DPP4 inhibition was evaluated in a mouse xenograft model.. High DPP4 expression was associated with extrathyroidal extension (P < 0.001), BRAF mutation (P < 0.001), and advanced tumor stage (P = 0.007) in papillary thyroid cancer. Patients in the high-DPP4 expression group were less likely to be classified as having no evidence of disease at final follow-up (P = 0.042). DPP4 silencing or treatment with DPP4 inhibitors significantly suppressed colony formation, cell migration, and invasion. Analysis of differentially expressed genes after DPP4 knockdown suggested that the transforming growth factor-β signaling pathway is involved. In vivo experiments revealed that sitagliptin treatment reduced tumor growth and xenograft transforming growth factor-β receptor I expression.. Increased DPP4 expression is associated with cellular invasion and more aggressive disease in papillary thyroid cancer. Targeting DPP4 may be a therapeutic strategy for DPP4-expressing thyroid cancer.

Topics: Adult; Animals; Blotting, Western; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Immunohistochemistry; In Vitro Techniques; Male; Mice; Middle Aged; Molecular Targeted Therapy; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; RNA, Small Interfering; Signal Transduction; Sitagliptin Phosphate; Thyroid Cancer, Papillary; Thyroid Neoplasms; Transforming Growth Factor beta; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

Dipeptidyl peptidase IV (DPPIV), also known as CD26, is a 110-kDa cell surface glycoprotein expressed in various tissues. DPPIV reportedly plays a direct role in the progression of several human malignancies. DPPIV specific inhibitors are employed as antidiabetics and could potentially be repurposed to enhance anti-tumor immunotherapies. In the present study, we investigated the correlation between DPPIV expression and tumor progression in endometrial carcinoma (EC). DPPIV overexpression altered cell morphology and stimulated cell proliferation, invasion and tumorigenesis in vitro and in vivo. These effects were abrogated by DPPIV knockdown or pharmacological inhibition using sitagliptin. DPPIV overexpression increased hypoxia-inducible factor 1a (HIF-1a) and vascular endothelial growth factor A (VEGFA) expression to promote HIF-1a-VEGFA signaling. Our results indicated that DPPIV accelerated endometrial carcinoma progression and that sitagliptin may be an effective anti-EC therapeutic.

Topics: Animals; Carcinoma; Cell Adhesion; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Shape; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endometrial Neoplasms; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin-Like Growth Factor I; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; RNA Interference; Signal Transduction; Sitagliptin Phosphate; Time Factors; Transfection; Vascular Endothelial Growth Factor A

The risk of pancreatic cancer associated with incretin-based therapies is controversial.. This study retrospectively analysed the National Health Insurance database including patients with newly diagnosed type 2 diabetes mellitus at an age ≥ 25 years between 1999 and 2010. A total of 71 137 ever users of sitagliptin and 933 046 never users were followed for pancreatic cancer until 31 December 2011. A time-dependent approach was used to calculate incidence and estimate hazard ratios adjusted for propensity score using Cox regression.. During follow-up, 83 ever users and 3658 never users developed pancreatic cancer, representing an incidence of 73·6 and 55·0 per 100 000 person-years, respectively. The adjusted hazard ratio (95% confidence intervals) for ever versus never users was 1·40 (1·13-1·75). The respective adjusted hazard ratio for the first, second and third tertile of cumulative dose < 14 700, 14 700-33 700 and > 33 700 mg was 1·83 (1·28-2·62), 1·97 (1·41-2·76) and 0·72 (0·45-1·15). For average daily dose of < 50, 50-99·9 and ≥ 100 mg, the respective hazard ratio was 3·10 (1·17-8·26), 1·01 (0·63-1·61) and 1·53 (1·18-1·97).. Sitagliptin is significantly associated with a higher risk of pancreatic cancer, especially when the cumulative dose is < 33 700 mg. The risk diminished in users with a higher cumulative dose. The daily dose of sitagliptin should better be kept < 100 mg, and its use should be reconsidered in patients who suffer from severe renal impairment and thus a daily dose of < 50 mg is always recommended. Future studies are required to confirm the findings with more appropriate adjustment for smoking.

Topics: Adult; Aged; Carcinoma; Carcinoma, Pancreatic Ductal; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incidence; Male; Middle Aged; Pancreatic Neoplasms; Propensity Score; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sitagliptin Phosphate; Taiwan

Dipeptidyl peptidase IV (DPPIV/CD26) is a transmembrane glycoprotein that inactivates or degrades some bioactive peptides and chemokines. For this reason, it regulates cell proliferation, migration and adhesion, showing its role in cancer processes. This enzyme is found mainly anchored onto the cell membrane, although it also has a soluble form, an enzymatically active isoform. In the present study, we investigated DPPIV/CD26 activity and expression in cervical cancer cell lines (SiHa, HeLa and C33A) and non-tumorigenic HaCaT cells. The effect of the DPPIV/CD26 inhibitor (sitagliptin phosphate) on cell migration and adhesion was also evaluated. Cervical cancer cells and keratinocytes exhibited DPPIV/CD26 enzymatic activity both membrane-bound and in soluble form. DPPIV/CD26 expression was observed in HaCaT, SiHa and C33A, while in HeLa cells it was almost undetectable. We observed higher migratory capacity of HeLa, when compared to SiHa. But in the presence of sitagliptin SiHa showed an increase in migration, indicating that, at least in part, cell migration is regulated by DPPIV/CD26 activity. Furthermore, in the presence of sitagliptin phosphate, SiHa and HeLa cells exhibited a significant reduction in adhesion. However this mechanism seems to be mediated independent of DPPIV/CD26. This study demonstrates, for the first time, the activity and expression of DPPIV/CD26 in cervical cancer cells and the effect of sitagliptin phosphate on cell migration and adhesion.

Topics: Carcinoma; Cell Adhesion; Cell Line, Tumor; Cell Membrane; Cell Movement; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; HeLa Cells; Humans; Keratinocytes; Membrane Glycoproteins; Sitagliptin Phosphate; Uterine Cervical Neoplasms