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Resveratrol promotes sensitization to Doxorubicin by inhibiting epithelial-mesenchymal transition and modulating SIRT1/?-catenin signaling pathway in breast cancer.

ABSTRACT: Breast cancer is one of the leading fatal diseases for women worldwide who cannot have surgery typically have to rely on systemic chemotherapy to extend their survival. Doxorubicin (DOX) is one of the most commonly used chemotherapeutic agents against breast cancer, but acquired resistance to DOX can seriously impede the efficacy of chemotherapy, leading to poor prognosis and recurrences of cancer. Resveratrol (RES) is a phytoalexin with pharmacological antitumor properties, but its underlying mechanisms are not clearly understood in the treatment of DOX-resistant breast cancer. We used cell viability assays, cell scratch tests, and transwell assays combined with Western blotting and immunofluorescent staining to evaluate the effects of RES on chemoresistance and the epithelial-mesenchymal transitions (EMTs) in adriamycin-resistant MCF7/ADR breast cancer cells, and to investigate its underlying mechanisms. The results showed that a treatment of RES combining with DOX effectively inhibited cell growth, suppressed cell migration, and promoted cell apoptosis. RES reversed EMT properties of MCF7/ADR cells by modulating the connection between SIRT1 and ?-catenin, which provides a hopeful therapeutic avenue to conquer DOX-resistance and thereby prolong survival rates in breast cancer patients.

SUBMITTER: Jin X

PROVIDER: S-EPMC6434195 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Resveratrol promotes sensitization to Doxorubicin by inhibiting epithelial-mesenchymal transition and modulating SIRT1/β-catenin signaling pathway in breast cancer.

Jin Xiaoxia X Wei Yingze Y Liu Yushan Y Lu Xiaoyun X Ding Fei F Wang Jiatai J Yang Shuyun S

Cancer medicine 20190129 3

Breast cancer is one of the leading fatal diseases for women worldwide who cannot have surgery typically have to rely on systemic chemotherapy to extend their survival. Doxorubicin (DOX) is one of the most commonly used chemotherapeutic agents against breast cancer, but acquired resistance to DOX can seriously impede the efficacy of chemotherapy, leading to poor prognosis and recurrences of cancer. Resveratrol (RES) is a phytoalexin with pharmacological antitumor properties, but its underlying m ...[more]

PMID: 30697969

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Project description:BackgroundThe ubiquitin E3 ligase activity has been ascribed to MID1, the causative gene of X-linked OS, and its homologue, MID2. Both alpha4, the common MID protein partner, and PP2Ac in MID-alpha4-PP2Ac complexes can be ubiquitylated. Ubiquitylation of alpha4 converted its function toward PP2Ac from protective to destructive, while PP2A also affected MID protein phosphorylation and their subsequent trafficking on microtubules. It was believed that disruption of the function of MID1-alpha4-PP2A complex was vital to the pathogenesis of craniofacial malformation, the most prominent clinical manifestation of OS, although the detailed molecular mechanisms was not unravelled.MethodsThe cellular level of PP2A and phosphor-PP2A in cells overexpressing MID1/MID2 or in cells with siRNA mediated MID1/MID2 gene silencing was analyzed using Western blot. The Wnt signaling in these cells was further monitored using TCF/LEF luciferase reporter assay and the cellular level of β-catenin was also verified using western blot. Given the crosstalk of E-cadherin and Wnt via the common effector β-catenin, the potential influences of MID1/MID2 on the cell migration and epithelial-mesenchymal transition (EMT) were investigated using wound healing assay and immunofluorescence for E-cadherin and vimentin, respectively.ResultsHere, we presented the increased phosphorylation of PP2Ac in cells overexpressing MID1/MID2, and vice versa, in vitro, while the cellular level of total PP2Ac was unaffected. In addition, β-catenin, the effector of canonical Wnt signaling, was downregulated in cells overexpressing MID1/MID2 and upregulated in cells with siRNA mediated MID1/MID2 gene silencing. Down-regulated Wnt/β-catenin signaling by Okadaic acid, a specific inhibitor of PP2A, was partially rescued by siRNA mediated MID1/MID2 gene silencing. In consistent, an activated EMT and accelerated cell migration in cells with MID1/MID2 gene silencing were observed, and vice versa.ConclusionsThe results in this study indicated roles for MID1 and MID2 in regulating cell migration/EMT via modulating Wnt/β-catenin signaling, which might help to understand the molecular etiology of the facial abnormalities that are usually the consequences of defective neural crest cells migration and EMT at the early stage of craniofacial development.

Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The epithelial-mesenchymal transition (EMT) is a critical stage during the development of fibrosis. To assess the effect of sulforaphane (SFN) on the EMT and fibrosis using an in vitro transforming growth factor (TGF)-?1-induced model and an in vivo bleomycin (BLM)-induced model.In vitro studies, cell viability, and cytotoxicity were measured using a Cell Counting Kit-8. The functional TGF-?1-induced EMT and fibrosis were assessed using western blotting and a quantitative real-time polymerase chain reaction. The lungs were analyzed histopathologically in vivo using hematoxylin and eosin and Masson's trichrome staining. The BLM-induced fibrosis was characterized by western blotting and immunohistochemical analyses for fibronectin, TGF-?1, E-cadherin (E-cad), and ?-smooth muscle actin (SMA) in lung tissues.SFN reversed mesenchymal-like changes induced by TGF-?1 and restored cells to their epithelial-like morphology. The results confirmed that the expression of the epithelial marker, E-cadherin, increased after SFN treatment, while expression of the mesenchymal markers, N-cadherin, vimentin, and ?-SMA decreased in A549 cells after SFN treatment. In addition, SFN inhibited TGF-?1-induced mRNA expression of the EMT-related transcription factors, Slug, Snail, and Twist. The SFN treatment attenuated TGF-?1-induced expression of fibrosis-related proteins, such as fibronection, collagen I, collagen IV, and ?-SMA in MRC-5 cells. Furthermore, SFN reduced the TGF-?1-induced phosphorylation of SMAD2/3 protein in A549 cells and MRC-5 cells. BLM induced fibrosis in mouse lungs that was also attenuated by SFN treatment, and SFN treatment decreased BLM-induced fibronectin expression, TGF-?1 expression, and the levels of collagen I in the lungs of mice.SFN showed a significant anti-fibrotic effect in TGF-?-treated cell lines and BLM-induced fibrosis in mice. These findings showed that SFN has anti-fibrotic activity that may be considered in the treatment of IPF.

Dataset Information

Resveratrol promotes sensitization to Doxorubicin by inhibiting epithelial-mesenchymal transition and modulating SIRT1/?-catenin signaling pathway in breast cancer.

Publications

Resveratrol promotes sensitization to Doxorubicin by inhibiting epithelial-mesenchymal transition and modulating SIRT1/β-catenin signaling pathway in breast cancer.

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