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

Han,Yujeong; Park,Sojung; Kinyua,Ann  W.; Andera,Ladislav; Kim,Ki  Woo; Kim,Inki

doi:10.3892/or.2013.2838

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

Authors:
- Yujeong Han
- Sojung Park
- Ann W. Kinyua
- Ladislav Andera
- Ki Woo Kim
- Inki Kim
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Affiliations: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea, Department of Pharmacology, Institute of Lifestyle Medicine and Nuclear Receptor Research Consortium, Yonsei University Wonju College of Medicine, Wonju 220-701, Republic of Korea, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague 4, Czech Republic
Published online on: November 7, 2013 https://doi.org/10.3892/or.2013.2838
Pages: 456-462

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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.

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