title: Tanshinone IIA induces TRAIL sensitization of human lung cancer cells through selective ER stress induction.
abstract: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promised anticancer medicine targeting only the tumor, most cancers show resistance to TRAIL-induced apoptosis. For this reason, new therapeutic strategies to overcome the TRAIL resistance are required for more effective tumor treatment. In the present study, potential of tanshinone IIA as a TRAIL sensitizer was evaluated in human non-small cell lung cancer (NSCLC) cells. NSCLC cells showed resistance to TRAIL-mediated cell death, but combination treatment of Tanshinone IIA and TRAIL synergistically decreased cell viability and increased apoptosis in TRAIL-resistant NSCLC cells. Tanshinone IIA greatly induced death receptor 5 (DR5), but not death receptor 4 (DR4). Furthermore, DR5 knockdown attenuated the combination treatment of tanshinone IIA with TRAIL-mediated cell death in human NSCLC cells. Tanshinone IIA also increased CHOP and activated the PERK-ATF4 pathway suggesting that tanshinone IIA increased DR5 and CHOP by activating the PERK-ATF4 pathway. Tanshinone IIA also downregulated phosphorylation of STAT3 and expression of survivin. Taken together, these results indicate that tanshinone IIA increases TRAIL-induced cell death via upregulating DR5 and downregulating survivin mediated by, respectively, selective activation of PERK/ATF4 and inhibition of STAT3, suggesting combinatorial intervention of tanshinone IIA and TRAIL as a new therapeutic strategy for human NSCLC.
authors.affiliation: Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul 02447, Republic of Korea.
authors.forename: Eun-Ok
authors.initials: EO
authors.lastname: Kim
authors.affiliation: Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Shi Eun
authors.initials: SE
authors.lastname: Kang
authors.affiliation: Department of Applied Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Chang Rak
authors.initials: CR
authors.lastname: Im
authors.affiliation: Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul 02447, Republic of Korea.
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Woong Mo
authors.initials: WM
authors.lastname: Yang
authors.affiliation: Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Um
authors.affiliation: Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul 02447, Republic of Korea.
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Miyong
authors.initials: M
authors.lastname: Yun
mesh_terms: D000072283:A549 Cells; D045784:Abietanes / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; C497249:DDIT3 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C021751:tanshinone; D051742:Transcription Factor CHOP