ZRANB2 and SYF2-mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to doxorubicin

Tanaka, Iris; Chakraborty, Alina; Saulnier, Olivier; Benoit‐Pilven, Clara; Vacher, Sophie; Labiod, Dalila; Lam, Eric W.‐F.; Bièche, Ivan; Delattre, Olivier; Pouzoulet, Frédéric; Auboeuf, Didier; Vagner, Stéphan; Dutertre, Martin

doi:10.1093/nar/gkz1213

Cited by 37 publications

(25 citation statements)

References 54 publications

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“…For instance, in non-small cell lung cancer, vasohibin2 (VASH2) functions as a tumor-promoting factor in enhancing proliferation that subsequently, stimulates DOX resistance [12]. Identification of such factors is of importance in suppressing DOX resistance by developing potential therapeutics for their targeting [13].…”

Section: Introductionmentioning

confidence: 99%

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

et al. 2021

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Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

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Section: Introductionmentioning

confidence: 99%

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

et al. 2021

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“…For instance, ES in FLNB has been reported to promote EMT in breast cancer by releasing the FOXC1 transcription factor and reducing FLNB nuclear localization [ 35 ]. Notably, scientists have found that high ECT2 splice variant including exon 5 (ECT2-Ex5+) levels was negatively related to prognosis in breast cancer treated with doxorubicin [ 36 ]. In short, aberrant ASEs play an important role in many biological processes, and these aberrant ASEs could serve as cancer hallmarkers or therapeutic targets in cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Systematic Profiling of mRNA Splicing Reveals the Prognostic Predictor and Potential Therapeutic Target for Glioblastoma Multiforme

Zhang

Cheng

et al. 2021

Journal of Oncology

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Despite many changes in alternative splicing events (ASEs) are frequently involved in various cancers, prognosis-related ASEs and drug treatment targets in glioblastoma multiforme (GBM) have not been well explored. ASEs participate in many biological behaviors in the initiation and progression of tumors, the aberrant ASE has been considered another hallmark of cancer, and the systematic study of alternative splicing may provide potential biomarkers for malignancies. In this study, we carried out a systematic analysis to characterize the ASE signatures in GBM cohort. Through comparing GBM tissues and nontumor tissues, a total of 48,191 differently expressed ASEs from 10,727 genes were obtained, and these aberrant ASEs play an important role in the oncogenic process. Then, we identified 514 ASEs independently associated with patient survival in GBM by univariate and multivariate Cox regression, including exon skip in CD3D, alternate acceptor site in POLD2, and exon skip in DCN. Those prognostic models built on ASEs of each splice type can accurately predict the outcome of GBM patients, and values for the area under curve were 0.97 in the predictive model based on alternate acceptor site. In addition, the splicing-regulatory network revealed an interesting correlation between survival-associated splicing factors and prognostic ASE corresponding genes. Moreover, these three hub splicing factors in splicing regulation network are the potential targets of some drugs. In conclusion, a systematic analysis of ASE signatures in GBM could serve as an indicator for identifying novel prognostic biomarkers and guiding clinical treatment.

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“…ECT2 has a relatively high expression level in different breast cancer cells and promotes tumour progression. 16 , 17 Mansour et al 16 reported that expression level of Ect2 may be a marker of TNBC, which can predict the invasion and metastasis of tumour. In our preliminary experiment, ECT2 was highly expressed in TNBC and associated with the prognosis of the disease.…”

Section: Discussionmentioning

confidence: 99%

<p>Effect of Ect2 Expression on the Growth of Triple-Negative Breast Cancer Cells with Paclitaxel Intervention</p>

Wang¹,

Liu²,

Li³

et al. 2020

OTT

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Object To identify the expression levels of ECT2 (epithelial cell transforming sequence 2) in triple-negative breast cancer (TNBC) before and after administration of paclitaxel (PTX) and explore the interaction between ECT2 and PTX in breast cancer treatment. Methods Lentiviral (LV) packaging ECT2 overexpression and interference plasmids were constructed for in vitro assays. The effects of ECT2 expression on the TNBC cell line (HCC1806), particularly its roles in the proliferation, invasion, migration and apoptosis and cell cycle, were evaluated using the CCK-8 and other methods before and after PTX treatment. In nude mouse xenograft settings were performed to detect cell apoptosis and Ki-67 expression levels by TUNEL and immunohistochemical staining, respectively. Results In the vitro assays, before and after the PTX treatment, comparison of the LV-ECT2 and sh-ECT2 groups and the remaining three groups (control, LV-NC, sh-NC) showed statistically significant differences in terms of cell proliferation, invasion and migration and apoptosis and changes in the cell cycle. In the vivo assays, the control, LV-ECT2 and sh-ECT2 groups markedly outweighed the corresponding PTX-treated groups. The LV-ECT2, PTX, sh-ECT2 and sh-ECT2-PTX were all significantly different from the control group in terms of body weight and tumour size changes. Cell apoptosis occurred in the PTX, sh-ECT2 and sh-ECT2-PTX groups. About the Ki-67 proliferation index, the PTX, LV-ECT2-PTX, sh-ECT2 and sh-ECT2-PTX groups were significantly different from the control group. Conclusion ECT2, which is a major driving factor in the growth of breast cancer cells, plays an important role in regulating TNBC growth. PTX therapy had significantly improved efficacy after silencing ECT2. This finding indicates that the inhibition of ECT2 expression may facilitate the treatment of breast cancer as a new regimen and provide a theoretical basis for the development of new targeted drugs as a replacement for PTX in breast cancer treatment.

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ZRANB2 and SYF2-mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to doxorubicin

Cited by 37 publications

References 54 publications

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Systematic Profiling of mRNA Splicing Reveals the Prognostic Predictor and Potential Therapeutic Target for Glioblastoma Multiforme

<p>Effect of Ect2 Expression on the Growth of Triple-Negative Breast Cancer Cells with Paclitaxel Intervention</p>

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