title: Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis.
abstract: 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.
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Eun Ah
authors.initials: EA
authors.lastname: Shin
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Sohn
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Gunho
authors.initials: G
authors.lastname: Won
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Jeong-Un
authors.initials: JU
authors.lastname: Choi
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Myongsuk
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Bonglee
authors.initials: B
authors.lastname: Kim
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Min-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D045784:Abietanes / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D045784:Abietanes; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C021751:tanshinone