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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
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SYSNO ASEP 0434383 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název 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 Tvůrce(i) Han, Y. (KR)
Park, S. (KR)
Kinyua, A.W. (KR)
Anděra, Ladislav (UMG-J) RID
Kim, K.W. (KR)
Kim, I. (KR)Zdroj.dok. Oncology Reports - ISSN 1021-335X
Roč. 31, č. 1 (2014), s. 456-462Poč.str. 7 s. Jazyk dok. eng - angličtina Země vyd. GR - Řecko Klíč. slova TRAIL ; Mcl-1 ; Pancreatic carcinoma Vědní obor RIV EB - Genetika a molekulární biologie CEP LH12202 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UMG-J - RVO:68378050 UT WOS 000330788100062 DOI 10.3892/or.2013.2838 Anotace 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. Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2015
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