title: Enhancement of paclitaxel-induced breast cancer cell death via the glycogen synthase kinase-3β-mediated B-cell lymphoma 2 regulation.
abstract: Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine protein kinase that is known to mediate cancer cell death. Here, we show that B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein, is regulated by GSK-3β and that GSK-3β-mediated regulation of Bcl-2 is crucial for mitochondrial-dependent cell death in paclitaxel-stimulated cells. We demonstrate that MCF7 GSK-3β siRNA cells are more sensitive to cell death than MCF7 GFP control cells and that in the absence of GSK-3β, Bcl-2 levels are reduced, a result enhanced by paclitaxel. Paclitaxel-induced JNK (c-Jun N-terminal kinase) activation is critical for Bcl-2 modulation. In the absence of GSK-3β, Bcl-2 was unstable in an ubiquitination-dependent manner in both basal- and paclitaxeltreated cells. Furthermore, we demonstrate that GSK-3β-mediated regulation of Bcl-2 influences cytochrome C release and mitochondrial membrane potential. Taken together, our data suggest that GSK-3β-dependent regulation of Bcl-2 is crucial for mitochondria-dependent cell death in paclitaxel-mediated breast cancer therapy.
authors.affiliation: Department of Infectious Diseases, Armed Forces Medical Research Institute, Daejeon 34059, Korea.
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Noh
authors.affiliation: Department of Immunology, KU Open Innovation Center, College of Medicine, Konkuk University, Chungju 27478, Korea.
authors.forename: Gil Sun
authors.initials: GS
authors.lastname: Cha
authors.affiliation: Department of Immunology, KU Open Innovation Center, College of Medicine, Konkuk University, Chungju 27478, Korea.
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.affiliation: Department of Neurosurgery, Konkuk University Hospital, Seoul 05030, Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Immunology, KU Open Innovation Center, College of Medicine, Konkuk University, Chungju 27478, Korea.
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Korea.
authors.forename: Kwang-Youn
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 50612, Korea.
authors.forename: Soon-Cheol
authors.initials: SC
authors.lastname: Ahn
authors.affiliation: National Research Laboratory of Molecular Virology, Department of Pathology, School of Medicine, The Catholic University of Korea, Seoul 03083, Korea.
authors.forename: Ji Chang
authors.initials: JC
authors.lastname: You
authors.affiliation: Department of Immunology, KU Open Innovation Center, College of Medicine, Konkuk University, Chungju 27478, Korea.
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D045304:Cytochromes c; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D017239:Paclitaxel