title: Apoptosis of mink lung epithelial cells by co-treatment of low-dose staurosporine and transforming growth factor-beta1 depends on the enhanced TGF-beta signaling and requires the decreased phosphorylation of PKB/Akt.
abstract: We demonstrate how co-treatment of low-dose staurosporine (STS) and TGF-beta1, which alone have little effect on cell death, markedly induces apoptosis in Mv1Lu mink lung epithelial cells, but not in its clonal variant R1B cells lacking functional TGF-beta signaling. This process was associated with mitochondria-dependent apoptosis and the enhanced TGF-beta/Smad signaling in Mv1Lu cells. When R1B cells were infected with adenovirus carrying wild-type ALK5, a functional TGF-beta type I receptor gene, the apoptotic cell death was significantly restored in these cells following co-treatment of low-dose STS and TGF-beta1. Treatment of Mv1Lu cells with both low-dose STS and TGF-beta1 decreased the activity of phospho-Akt, which is involved in cell survival signal. In addition, pre-treatments of PI3 kinase inhibitors, LY294002 and wortmannin, further increased the apoptosis of MvlLu cells induced by co-treatment of low-dose STS and TGF-beta1. And overexpression of constitutively active Akt (myr-Akt) using adenoviral expression system inhibited the apoptotic cell death of Mv1Lu cells by about 50% upon co-treatment of low-dose STS and TGF-beta1. These results suggest that co-treatment of low-dose STS and TGF-beta1 induces apoptosis of mink lung epithelial cells by enhancing TGF-beta signaling and in part suppressing cytoprotective signaling.
authors.affiliation: Research Institute, National Cancer Center, Goyang, Gyeonggi 411-769, Republic of Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Ju
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Hong
authors.forename: Chang-Hun
authors.initials: CH
authors.lastname: Lee
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Kim
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: In-Hoo
authors.initials: IH
authors.lastname: Kim
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D008907:Mink; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019311:Staurosporine / Q000008:administration & dosage*; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D004338:Drug Combinations; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine