title: Involvement of phosphatidylinositol 3-kinase/Akt pathway in gemcitabine-induced apoptosis-like cell death in insulinoma cell line INS-1.
abstract: This study demonstrated gemcitabine-induced cytotoxicity in the insulinoma cell line INS-1. Gemcitabine inhibited INS-1 cell proliferation and maintained consistent cell number for 24 h, and then caused apoptosis within 48 h of incubation. Since gemcitabine activates the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, which is involved in the resistance of pancreatic exocrine cancer to gemcitabine, we investigated the participation of this pathway in gemcitabine-induced cytotoxicity in INS-1 cells. LY294002 and wortmannin, two PI3-K inhibitors, significantly prevented gemcitabine-induced cytotoxicity in INS-1 cells, indicating that the PI3-K/Akt pathway is involved in gemcitabine-induced cytotoxicity. Gemcitabine-induced Akt phosphorylation in INS-1 cells was prevented by LY294002. Although gemcitabine induced cell cycle arrest at the G1 and early S phases, LY294002 did not inhibit the cell cycle. These data suggest that PI3-K activation does not influence gemcitabine-induced cell cycle arrest. In gemcitabine-treated cells, nuclear fragmentation and DNA ladder formation were observed. These findings suggest that gemcitabine induced apoptotic cell death in INS-1 cells through the activation of the PI3-K/Akt pathway.
authors.affiliation: Division of Biochemistry, Department of Life Science, School of Pharmacy, Hokkaido Pharmaceutical University, 7–1 Katsuraoka-cho, Otaru, Hokkaido 047–0264, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Motoshige
authors.forename: Kyohei
authors.initials: K
authors.lastname: Oyama
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Sakurai
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007340:Insulinoma; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077191:Wortmannin; D000093542:Gemcitabine
chemical_list: D000730:Androstadienes; D000964:Antimetabolites, Antineoplastic; D002867:Chromones; D009025:Morpholines; D003841:Deoxycytidine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546845:mTOR protein, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000077191:Wortmannin; D000093542:Gemcitabine