title: LKB1 is crucial for TRAIL-mediated apoptosis induction in osteosarcoma.
abstract: Despite improvements in chemotherapy and surgery in the treatment of osteosarcoma, satisfactory results are still difficult to achieve. New therapeutic modalities need to be developed for the improvement of these treatments. TRAIL (TNF-related apoptosis inducing ligand) is known as a selective apoptosis inducer in most tumor cells, but not in normal cells. Therefore, TRAIL is a good candidate target for the treatment of tumors. However, sensitivity of osteosarcoma cells to TRAIL-induced apoptosis is lower than that of other types of tumor cells. Recently, DAP3 (death associated protein 3) was demonstrated to play a critical role in TRAIL-mediated apoptosis through activation of pro-caspase-8. Here, we found that LKB1, a serine/threonine kinase, expressed in bone and soft tissue sarcoma cells, associated with DAP3. We also demonstrated that expression of DAP3 induced apoptosis in osteosarcoma cells. Furthermore, expression of LKB1 induced apoptosis and co-expression of LKB1 with DAP3 strongly induced apoptosis in osteosarcoma cells. In addition, expression of LKB1 kinase dead mutant, LKB1 (K78M), inhibited DAP3-induced apoptosis in these cells. These results suggest that LKB1 is critical for TRAIL-induced apoptosis induction, cooperating with DAP3 in osteosarcoma cells. It is predicted that LKB1 and DAP3 could be critical target molecules for the treatment of osteosarcomas.
authors.affiliation: Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Takeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwai
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujikura
authors.forename: Satoko
authors.initials: S
authors.lastname: Chiba
authors.forename: Hong Mei
authors.initials: HM
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Uehara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawaguchi
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Kaya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagoya
authors.forename: Takuro
authors.initials: T
authors.lastname: Wada
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Sydonia
authors.initials: S
authors.lastname: Rayter
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yamashita
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D041681:NIH 3T3 Cells; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013268:Stimulation, Chemical; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; C097041:DAP3 protein, human; D007527:Isoenzymes; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D020169:Caspases