title: PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway.
abstract: Although preclinical work with rapalogs suggests potential in the treatment of gastric cancer, they have been less successful clinically. In this study, we report the impact of the investigational drug PP242, a potent and selective small-molecule active-site TORC1/2 kinase inhibitor, on tumor growth and metastasis. The antiproliferative effect of PP242 was assessed using the Cell Counting Kit-8 assay. The migration and invasion potential were analyzed using wound-healing and transwell assays, respectively. The Matrigel capillary tube formation assay was performed to mimic in-vivo angiogenesis. Immunoblotting and immunofluorescence were used to observe protein levels and distribution of actin fibers. Finally, p-mammalian target of rapamycin (mTOR) expression was detected on gastric cancer tissues using immunohistochemistry. First, PP242 potently inhibited cell proliferation in gastric cancer cell lines and in human endothelial cells in vitro at the IC50 ranged from 50 to 500 nmol/l. Then, an inhibitory effect of PP242 on metastasis was observed in gastric cancer cell AGS, along with the cytoskeletal rearrangements and suppression of the phosphorylation of PI3K downstream factors including AKT, mTOR, and P70S6K. Furthermore, PP242 was found to decrease the tube formation and migration of human umbilical vein endothelial cells. Using immunohistochemistry, we found that p-mTOR staining was observed in 41.8% (82/196) of gastric cancer tissues and correlated with depth of mural invasion, lymph node metastasis, tumor node metastasis stage, and vascular invasion. These results show that PP242 suppresses cell proliferation and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway, which might be an effective novel therapeutic candidate against gastric cancer in the future.
authors.affiliation: Departments of aGastrointestinal Translational Research bGastrointestinal Surgery cTissue Bank dPathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University, Beijing Cancer Hospital & Institute, Beijing, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Xing
authors.forename: Lianhai
authors.initials: L
authors.lastname: Zhang
authors.forename: Xianzi
authors.initials: X
authors.lastname: Wen
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Cheng
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Dong
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Li
authors.forename: Jiafu
authors.initials: J
authors.lastname: Ji
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology*; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000098:blood supply / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D011687:Purines; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C572919:PP242