title: Emetine enhances the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of pancreatic cancer cells by downregulation of myeloid cell leukemia sequence-1 protein.
abstract: Although the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent, it shows limited efficacy in human pancreatic cancer cells. Protein synthesis inhibition has been reported to sensitize cancer cells to apoptosis-inducing agents, but the detailed mechanism by which protein synthesis inhibition sensitize cells to TRAIL has not been determined. To investigate the mechanism underlying pancreatic cancer cell resistance to TRAIL, we performed a small scale high-throughput compound screening in AsPC-1 pancreatic cancer cells using a bioactive small molecule library. We identified 8 compounds that reproducibly sensitize AsPC-1 cells to TRAIL-induced apoptosis. One of these compounds, emetine hydrochloride, when combined with subtoxic concentrations of TRAIL, induced massive apoptosis in AsPC-1 and BxPC-3 pancreatic cancer cells. Cell death analysis revealed that the sensitizing effects of emetine were specific to TRAIL. Emetine downregulated the expression of the TRAIL-related anti-apoptotic protein Mcl-1 in a dose- and time-dependent manner. Furthermore, specific knockdown of Mcl-1 using small interfering RNA without emetine treatment sensitized pancreatic cancer cells to TRAIL. Emetine sensitization of pancreatic cancer cells to TRAIL via Mcl-1 was confirmed under hypoxic conditions. Taken together, these findings strongly suggest that Mcl-1 is involved in pancreatic cancer cell resistance to TRAIL, and emetine facilitates the apoptosis of TRAIL-tolerant pancreatic cancer cells by specifically inhibiting Mcl-1 function.
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Yujeong
authors.initials: Y
authors.lastname: Han
authors.forename: Sojung
authors.initials: S
authors.lastname: Park
authors.forename: Ann W
authors.initials: AW
authors.lastname: Kinyua
authors.forename: Ladislav
authors.initials: L
authors.lastname: Andera
authors.forename: Ki Woo
authors.initials: KW
authors.lastname: Kim
authors.forename: Inki
authors.initials: I
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004640:Emetine / Q000494:pharmacology*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D004640:Emetine