Research Article Details

Article ID: A12334
PMID: 30510994
Source: Cell Mol Gastroenterol Hepatol
Title: Dipeptidyl Peptidase 4 Inhibitors Reduce Hepatocellular Carcinoma by Activating Lymphocyte Chemotaxis in Mice.
Abstract: Background & Aims: CD26, a multifunctional transmembrane glycoprotein, is expressed in various cancers and functions as dipeptidyl peptidase 4 (DPP4). We investigated whether CD26 expression is associated with hepatocellular carcinoma (HCC) progression and whether DPP4 inhibitors exert antitumor effects against HCC. Methods: CD26 expression was examined in 41 surgically resected HCC specimens. The effects of DPP4 inhibitors on HCC were examined by using HCC cell lines (Huh-7 and Li-7), xenograft tumors in nude mice, and a nonalcoholic steatohepatitis-related HCC mouse model. Results: CD26 expression in HCC specimens was associated with increased serum DPP4 activity, as well as a more advanced stage, less tumor immunity, and poorer prognosis in HCC patients. The HCC cell lines and xenograft tumors exhibited CD26 expression and DPP4 activity. The DPP4 inhibitors did not exhibit antitumor effects in vitro, but natural killer (NK) and/or T-cell tumor accumulation suppressed growth of xenograft tumor and HCC in vivo. The antitumor effects of DPP4 inhibitors were abolished by the depletion of NK cells or the neutralization of CXCR3, a chemokine receptor on NK cells. EZ-TAXIScan, an optical horizontal chemotaxis apparatus, identified enhanced NK and T-cell chemotaxis by DPP4 inhibitors ex vivo in the presence of Huh-7 cells and the chemokine CXCL10, which binds to CXCR3. The DPP4 inhibitors prevented the biologically active form of CXCL10 from being truncated by Huh-7 cell DPP4 activity. DPP4 inhibitors also suppressed tumor angiogenesis. Conclusions: These results provide a rationale for verifying whether DPP4 inhibitors clinically inhibit the progression of HCC or augment the antitumor effects of molecular-targeting drugs or immunotherapies against HCC.
DOI: 10.1016/j.jcmgh.2018.08.008

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T18 Acetyl-CoA carboxylase 1 ACACA inhibitor Enzyme Q13085 ACACA_HUMAN Details
T10 Caspase-1 CASP1 inhibitor Enzyme P29466 CASP1_HUMAN Details
T03 Peroxisome proliferator-activated receptor alpha PPARA agonist Nuclear hormone receptor Q07869 PPARA_HUMAN Details
T21 Diacylglycerol O-acyltransferase 2 DGAT2 inhibitor Enzyme Q96PD7 DGAT2_HUMAN Details

Diseases ID DO ID Disease Name Definition Class
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D550 DPP4 inhibitor Chemical drug -- DPP4 inhibitor -- Under clinical trials Details
D328 Serine Chemical drug DB00133 SRR Improve insulin resistance Under clinical trials Details
D010 Amoxicillin Chemical drug DB01060 -- -- Under clinical trials Details
D338 Sitagliptin Chemical drug DB01261 DPP4 inhibitor Antidiabetic drug Under clinical trials Details
D083 CLA Chemical drug DB01211 KCNH2; SLCO1B1; SLCO1B3 -- Under clinical trials Details
D383 Vildagliptin Chemical drug DB04876 DPP4 inhibitor Antidiabetic drug Under clinical trials Details