title: Anti-tumor peptide AP25 decreases cyclin D1 expression and inhibits MGC-803 proliferation via phospho-extracellular signal-regulated kinase-, Src-, c-Jun N-terminal kinase- and phosphoinositide 3-kinase-associated pathways.
abstract: The anti-tumor peptide AP25 is a prototype integrin antagonist, which exhibits anti‑angiogenic and anti‑tumor activity. The molecular mechanisms by which AP25 inhibits the growth of the MGC‑803 gastric carcinoma cell line were investigated in the present study. K‑ras specific RNA interference by lentiviral infection was successfully induced in MGC‑803 cells [MGC‑803 short hairpin (sh)RNA group] and the expression levels of K‑ras, phosphorylated extracellular signal‑regulated kinase (p-ERK) and cyclin D1 were observed to be markedly decreased. By contrast, AP25 caused cell cycle arrest of intact MGC‑803 cells and decreased p‑ERK and cyclin D1 expression levels. Of note, 0.4‑3.2 µM AP25 no longer inhibited MGC‑803 shRNA growth, indicating that AP25, at such concentrations, exerts its effect mainly through the Ras/Raf/mitogen-activated protein kinase kinase/ERK pathway, whereas at 25 µM, AP25 was able to inhibit MGC‑803 shRNA growth. Chemical inhibitors of Src, c‑Jun N‑terminal kinase (JNK) and phosphoinositide 3‑kinase (PI3K) were used to confirm that 25 µM AP25 inhibited growth of cells in the MGC‑803 shRNA group and activated intracellular signaling pathways with Src, JNK and PI3K as key enzymes. In conclusion, the present study revealed the signal transduction pathways activated by AP25 at low (0.4‑3.2 µM) or high (25 µM) concentrations. It also confirmed that integrins, when interacting with the freely moving ligand AP25 instead of immobilized extracellular matrix glycoproteins, are able to initiate cell signaling via similar pathways as in the latter case but with a reversed effect, to inhibit cell growth.
authors.affiliation: Key Laboratory of Modern Chinese Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, Jiangsu 211198, P.R. China.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Key Laboratory of Modern Chinese Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, Jiangsu 211198, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Modern Chinese Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, Jiangsu 211198, P.R. China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Liver Transplant Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Beicheng
authors.initials: B
authors.lastname: Sun
authors.affiliation: Liver Transplant Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.affiliation: Key Laboratory of Modern Chinese Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, Jiangsu 211198, P.R. China.
authors.forename: Hanmei
authors.initials: H
authors.lastname: Xu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D043169:Endostatins / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C000607498:AP25 peptide; D020533:Angiogenesis Inhibitors; C530104:CCND1 protein, human; D043169:Endostatins; D010446:Peptide Fragments; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases