A New <sup>18</sup>F-Labeled Myocardial PET Tracer: Myocardial Uptake After Permanent and Transient Coronary Occlusion in Rats
Etoposide is regarded as one of the main standard cytotoxic drugs for lung cancer. However, mutations in Kelch-like ECH-associated protein 1 (<i>Keap1</i>), the main regulator of nuclear factor erythroid 2-related factor 2 (Nrf2), are often detected in lung cancer and lead to chemoresist...
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| Main Authors: | , , , , , , , , , , |
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| 格式: | Artigo |
| 語言: | 英语 |
| 出版: |
2008
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| 在線閱讀: | https://doi.org/10.2967/jnumed.108.053967 http://jnm.snmjournals.org/content/49/10/1715.full.pdf |
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| 總結: | Etoposide is regarded as one of the main standard cytotoxic drugs for lung cancer. However, mutations in Kelch-like ECH-associated protein 1 (<i>Keap1</i>), 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 <i>Keap1</i> loss-of-function mutation. A treatment with <i>β</i>-glucan, a major component of the fungal cell wall, reduced Nrf2 protein levels; downregulated the expression of cytochrome P450 <i>3A5</i>, UDP glucuronosyltransferase <i>1A1,</i> 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 <i>β</i>-glucan in A549 cells. EphA2 signaling includes nuclear factor kappa B (NF-<i>κ</i>B), 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 <i>β</i>-glucan. In contrast, knockdown of v-rel reticuloendotheliosis viral oncogene homolog B (RelB) abolished the effects of <i>β</i>-glucan, suggesting the involvement of the noncanonical NF-<i>κ</i>B pathway. The <i>β</i>-glucan effects were also attenuated by the knockdown of WD40 Repeat protein 23 (WDR23). The <i>β</i>-glucan treatment and RelB overexpression induced the expression of Cullin-4A (<i>CUL4A</i>), which increased WDR23 ligase activity and promoted the subsequent depletion of Nrf2. These results revealed a novel property of <i>β</i>-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. <h3>SIGNIFICANCE STATEMENT</h3> 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. |
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