title: RAD001 (everolimus) enhances TRAIL cytotoxicity in human leukemic Jurkat T cells by upregulating DR5.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anti-cancer agents, is a promising new strategy for the treatment of cancer. However, aberrant PI3K/Akt/mTOR survival signaling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. In the present study, we showed that the Akt/mTOR inhibitor RAD001 (everolimus) induced cell death in a dose-dependent manner and enhanced TRAIL-induced apoptosis in human leukemic Jurkat T cells, which show PI3K/Akt/mTOR pathway activation and basal expression levels of death receptor (DR) 5 (TRAIL-R2). Investigation of the effect of RAD001 treatment on the expression of TRAIL receptors (TRAIL-Rs) in Jurkat T cells showed that RAD001 significantly upregulated DR5 by up to 51.22%, but not other TRAIL-Rs such as DR4 (TRAIL-R1), decoy receptor (DcR) 1 (TRAIL-R3), and DcR2 (TRAIL-R4). Pretreatment with DR5:Fc chimera abrogated the RAD001-induced increase of TRAIL cytotoxicity, indicating that the upregulation of DR5 by RAD001 plays a role in enhancing the susceptibility of Jurkat T cells to TRAIL. Our results indicate that combination treatment with RAD001 and TRAIL may be a novel therapeutic strategy in leukemia.
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Myoung Woo
authors.initials: MW
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Dae Seong
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Eom
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Young Jong
authors.initials: YJ
authors.lastname: Ko
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Ki Woong
authors.initials: KW
authors.lastname: Sung
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. Electronic address: hhkoo@skku.edu.
authors.forename: Hong Hoe
authors.initials: HH
authors.lastname: Koo
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, South Korea. Electronic address: hema2170@skku.edu.
authors.forename: Keon Hee
authors.initials: KH
authors.lastname: Yoo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000473:pathology* / Q000503:physiopathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000068338:Everolimus; D020123:Sirolimus
keywords: Apoptosis; Death receptor; Leukemic cells; RAD001 (everolimus); TRAIL