論文 - 詳細
| RRC ID | 71614 |
|---|---|
| 著者 | Siswanto FM, Tamura A, Sakuma R, Imaoka S. |
| タイトル | Yeast β-glucan Increases Etoposide Sensitivity in Lung Cancer Cell Line A549 by Suppressing Nuclear Factor Erythroid 2-Related Factor 2 via the Noncanonical Nuclear Factor Kappa B Pathway. |
| ジャーナル | Mol Pharmacol |
| Abstract |
Etoposide is regarded as one of the main standard cytotoxic drugs for lung cancer. However, mutations in Kelch-like ECH-associated protein 1 (Keap1), the main regulator of nuclear factor erythroid 2-related factor 2 (Nrf2), are often detected in lung cancer and lead to chemoresistance. Since the aberrant activation of Nrf2 enhances drug resistance, the suppression of the Nrf2 pathway is a promising therapeutic strategy for lung cancer. We herein used the human lung adenocarcinoma cell line A549 because it harbors a Keap1 loss-of-function mutation. A treatment with β-glucan, a major component of the fungal cell wall, reduced Nrf2 protein levels; downregulated the expression of cytochrome P450 3A5, UDP glucuronosyltransferase 1A1, and multidrug resistance protein 1; and increased etoposide sensitivity in A549 cells. Furthermore, the ephrin type-A receptor 2 (EphA2) receptor was important for the recognition and biologic activity of β-glucan in A549 cells. EphA2 signaling includes nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and p38 mitogen-activated protein kinase (MAPK). However, treatment of cells with stattic (STAT3 inhibitor) or SB203580 (p38 MAPK inhibitor) did not diminish the effects of β-glucan. In contrast, knockdown of v-rel reticuloendotheliosis viral oncogene homolog B (RelB) abolished the effects of β-glucan, suggesting the involvement of the noncanonical NF-κB pathway. The β-glucan effects were also attenuated by the knockdown of WD40 Repeat protein 23 (WDR23). The β-glucan treatment and RelB overexpression induced the expression of Cullin-4A (CUL4A), which increased WDR23 ligase activity and promoted the subsequent depletion of Nrf2. These results revealed a novel property of β-glucan as a resistance-modifying agent in addition to its widely reported immunomodulatory effects for lung cancer therapy via the EphA2-RelB-CUL4A-Nrf2 axis. SIGNIFICANCE STATEMENT: Chemotherapeutic resistance remains a major obstacle in cancer therapy despite extensive efforts to elucidate the underlying molecular mechanisms and overcome multidrug resistance. The present study revealed a novel resistance-modifying property of β-glucan, thereby expanding our knowledge on the beneficial roles of β-glucan and providing an alternative strategy to prevent drug resistance by cancer. The present results provide evidence for the involvement of a novel mode of NF-κB and Nrf2 crosstalk in the drug resistance phenotype. |
| 巻・号 | 101(4) |
| ページ | 257-273 |
| 公開日 | 2022-4-1 |
| DOI | 10.1124/molpharm.121.000475 |
| PII | molpharm.121.000475 |
| PMID | 35193967 |
| MeSH | A549 Cells Cullin Proteins / metabolism Etoposide / pharmacology Humans Kelch-Like ECH-Associated Protein 1 / genetics Lung Neoplasms* / drug therapy NF-E2-Related Factor 2 / metabolism NF-kappa B / metabolism Saccharomyces cerevisiae / metabolism beta-Glucans* / pharmacology p38 Mitogen-Activated Protein Kinases / metabolism |
| IF | 3.664 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | A549(RCB0098) |