Tanshinone IIA induces TRAIL sensitization of human lung cancer cells through selective ER stress induction
| Autor: | Eun-Ok Kim, Junhee Lee, Woong Mo Yang, Kwang Seok Ahn, Shi Eun Kang, Miyong Yun, Chang Rak Im, Jae-Young Um, Seok-Geun Lee |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research Programmed cell death medicine.medical_specialty Lung Neoplasms Cell Survival Cell Apoptosis CHOP TNF-Related Apoptosis-Inducing Ligand 03 medical and health sciences 0302 clinical medicine Internal medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor Survivin Medicine Humans A549 cell Oncogene business.industry Drug Synergism Cell cycle Endoplasmic Reticulum Stress Antineoplastic Agents Phytogenic Gene Expression Regulation Neoplastic Receptors TNF-Related Apoptosis-Inducing Ligand 030104 developmental biology medicine.anatomical_structure A549 Cells Drug Resistance Neoplasm 030220 oncology & carcinogenesis Abietanes Cancer research business Transcription Factor CHOP |
| Zdroj: | International journal of oncology. 48(5) |
| ISSN: | 1791-2423 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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