Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis

Though tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used as a potent anticancer agent, TRAIL resistance is a hot-issue in cancer therapy. We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and...

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Veröffentlicht in:Oncotarget 2014-07, Vol.5 (14), p.5624-5636
Hauptverfasser: Shin, Eun Ah, Sohn, Eun Jung, Won, Gunho, Choi, Jeong-Un, Jeong, Myongsuk, Kim, Bonglee, Kim, Min-Jeong, Kim, Sung-Hoon
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container_end_page 5636
container_issue 14
container_start_page 5624
container_title Oncotarget
container_volume 5
creator Shin, Eun Ah
Sohn, Eun Jung
Won, Gunho
Choi, Jeong-Un
Jeong, Myongsuk
Kim, Bonglee
Kim, Min-Jeong
Kim, Sung-Hoon
description Though tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used as a potent anticancer agent, TRAIL resistance is a hot-issue in cancer therapy. We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and TRAIL exerted synergistic cytotoxicity, increased cleaved PARP, sub G1 population, the number of TUNELpositive cells, activated caspase 8, 9 and ROS production in PC-3 and DU145 cells. Of note, combination of Tanshinone I and TRAIL enhanced the protein expression of death receptor 5 (DR5) and attenuated anti-apoptotic proteins. RT-PCR and RT-qPCR analyses confirmed that co-treatment of Tanshinone I and TRAIL up-regulated DR5 and microRNA 135a-3p at mRNA level or activity of DR5 promoter and attenuated phosphorylation of extracellular signal regulated kinases in PC-3. Conversely, the silencing of DR5 blocked the increased cytotoxicity, sub G1 population and PARP cleavages induced by co-treatment of Tanshinone I and TRAIL. Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3. Overall, our findings suggest that Tanshinone I enhances TRAIL mediated apoptosis via upregulation of miR135a-3p mediated DR5 in prostate cancer cells as a potent TRAIL sensitizer.
doi_str_mv 10.18632/oncotarget.2152
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We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and TRAIL exerted synergistic cytotoxicity, increased cleaved PARP, sub G1 population, the number of TUNELpositive cells, activated caspase 8, 9 and ROS production in PC-3 and DU145 cells. Of note, combination of Tanshinone I and TRAIL enhanced the protein expression of death receptor 5 (DR5) and attenuated anti-apoptotic proteins. RT-PCR and RT-qPCR analyses confirmed that co-treatment of Tanshinone I and TRAIL up-regulated DR5 and microRNA 135a-3p at mRNA level or activity of DR5 promoter and attenuated phosphorylation of extracellular signal regulated kinases in PC-3. Conversely, the silencing of DR5 blocked the increased cytotoxicity, sub G1 population and PARP cleavages induced by co-treatment of Tanshinone I and TRAIL. Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3. 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subjects Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis - drug effects
Cell Line, Tumor
Diterpenes, Abietane - administration & dosage
Diterpenes, Abietane - pharmacology
Drug Synergism
Humans
Male
MicroRNAs - biosynthesis
MicroRNAs - genetics
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Reactive Oxygen Species - metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand - biosynthesis
Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics
Research Paper
TNF-Related Apoptosis-Inducing Ligand - administration & dosage
TNF-Related Apoptosis-Inducing Ligand - pharmacology
Transfection
Up-Regulation
title Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis
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