Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling

Zhu, Xue; Zou, Wen-Jun; Meng, Xinmin; Ji, Jiali; Wang, Xun; Shu, Hong; Chen, Yuan; Pan, Donghui; Wang, Ke; Zhou, Fanfan

doi:10.3389/fonc.2022.788496

Cited by 10 publications

(18 citation statements)

References 57 publications

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“…Body weight and tumor volumes were measured every other day. After treatment, the mice were intraperitoneally injected with D-luciferin working solution (15 mg/mL) and image analysis was performed using the Xenogen Living Image system (Alameda, CA, USA) [ 43 ]. Then, the tumors were removed, weighed and photographed.…”

Section: Methodsmentioning

confidence: 99%

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Erdafitinib Inhibits Tumorigenesis of Human Lung Adenocarcinoma A549 by Inducing S-Phase Cell-Cycle Arrest as a CDK2 Inhibitor

Meng

Zhu

et al. 2022

Molecules

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Lung adenocarcinoma (LADC) is the most prevalent lung cancer sub-type, and targeted therapy developed in recent years has made progress in its treatment. Erdafitinib, a potent and selective pan-FGFR tyrosine kinase inhibitor, has been confirmed to be effective for the treatment of LADC; however, the molecular mechanism responsible for this effect is unclear. The in vitro study showed that erdafitinib exhibited an outstanding anti-cancer activity in human LADC cell line A549 by inducing S-phase cell-cycle arrest and cell apoptosis. The mechanistic study based on the transcriptomic data revealed that erdafitinib exerted its anti-cancer effect by affecting the cell cycle-related pathway, and CDK2 was the regulatory target of this drug. In addition, CDK2 overexpression significantly attenuated the anti-cancer effect of erdafitinib by affecting the transcriptional activity and expression of E2F1, as well as the expression of CDK1. The in vivo study showed that erdafitinib presented an obvious anti-cancer effect in the A549 xenograft mice model, which was accompanied by the reduced expression of CDK2. Thus, this study demonstrates the anti-cancer effect of erdafitinib against LADC for the first time based on in vitro and in vivo models, whose activity is achieved by targeting CDK2 and regulating downstream E2F1-CDK1 signaling. This study may be helpful for expanding the clinical application of erdafitinib in treating LADC.

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Section: Methodsmentioning

confidence: 99%

“…After treatment, the tumor tissues were embedded in paraffin and cut into 8 mm-thick sections. Then, H&E, TUNEL and Ki67 staining was performed using tumor sections [ 43 ]. Then, the expression of CDK2 was assessed using immunohistochemical staining.…”

Section: Methodsmentioning

confidence: 99%

Erdafitinib Inhibits Tumorigenesis of Human Lung Adenocarcinoma A549 by Inducing S-Phase Cell-Cycle Arrest as a CDK2 Inhibitor

Meng

Zhu

et al. 2022

Molecules

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“…The anti-UM actions of lapatinib were examined further in a xenograft model 47 Lapatinib was administered to nude mice that carried UM cell xenografts at a dose of 25mg/kg for 14 d; tumour growth was suppressed (Fig. 8A and 8B).…”

Section: Lapatinib Has Potent Anti-tumour Activity In a Um Xenograft ...mentioning

confidence: 99%

“…TUNEL assay was used to detect cell death in paraffin-embedded tumour sections. Briefly, sections were placed on slides and stained with the TUNEL assay kit (Beyotime Institute of Biotechnology, Jiangsu, China), as described previously 47 ; nuclei were counter-stained with hematoxylin. Images were analysed using a KF-PRO-120 slide scanner (Konfoong Bioinformation Tech, Ningbo, China).…”

Section: Tunel Assaymentioning

confidence: 99%

Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells

Shu

Wang

Zhu

et al. 2022

Preprint

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Although uveal melanoma (UM) is rare, it is the principal type of intraocular malignancy. Up to 50% of UM patients develop metastatic disease with low chances of survival beyond 18 months. At present there are no drugs that are effective in the treatment of primary or metastatic disease. We recently tested the hypothesis that the ErbB receptor family member HER2 may be a novel drug target in UM. We found that afatinib, which targets several ErbB receptors, including HER2, has potent anti-cancer and anti-metastatic actions in UM. The present study was undertaken to further evaluate the potential value of HER2 targeting in UM using the multi-kinase inhibitor lapatinib, that is currently approved for the treatment of HER2-positive cancers in patients. The anti-UM actions of lapatinib were assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing and colony formation assays. Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling. The anti-UM actions of lapatinib were further evaluated in vivo in a UM xenograft mouse model. Lapatinib decreased the viability of four UM cell lines (IC50 values in MTT reduction assays were 3.67-6.53 µM). The antiproliferative activity of lapatinib was corroborated in UM cells isolated from patient tumors. In UM cell lines lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration and reproductive cell growth. Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling in UM cell lines, as indicated by increased STAT1 expression, decreased expression of BCL-xL and cyclin D1, and decreased Bcl-xL:Bax ratio, which is consistent with enhanced apoptosis. Importantly, lapatinib and suppressed tumourigenesis in vivo in mice carrying UM cell xenografts. Together the present findings are consistent with the assertion that HER2 is a viable therapeutic target in UM. Lapatinib was active in primary and metastatic UM and is a clinically approved HER2 inhibitor. The activity of lapatinib in UM patients could now be evaluated directly in clinical trials.

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“…In addition to protein aggregates, mitochondria can be targeted for selective autophagic degradation by virtue of ubiquitin tags on their outer surfaces, and this autophagic process is commonly referred to as the PINK1–Parkin pathway of mitophagy. Our previous study has shown that elaiophylin exhibits outstanding anti-cancer activity in human uveal melanoma (UM) cell lines and human UM primary cells through suppressing mitophagy, inducing oxidative stress leading to autophagic cell death [ 8 ]. Elaiophylin acts on SIRT1 in uveal melanoma cells and consequently impacts on the deacetylation and mitochondrial localization of FoxO3a [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling

Wang

Meng

et al. 2022

Cancers

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Lung adenocarcinoma (LADC), the most common type of lung cancer, is still one of the most aggressive and rapidly fatal tumor types, even though achievements in new therapeutic approaches have been developed. Elaiophylin as a C2 symmetrically glycosylated 16 macrolides has been reported to be a late-stage autophagy inhibitor with a potent anti-tumor effect on various cancers. This study investigated the anti-tumor effect of elaiophylin on human LADC for the first time in in vitro and in vivo models. The in vitro study in LADC A549 cells showed that elaiophylin significantly inhibited cell viability and induced cell apoptosis through the suppression of mitophagy and induction of cellular and mitochondrial oxidative stress. Proteomic analysis and molecular docking assay implicated that SIRT1 was likely the direct target of elaiophylin in A549 cells. Further mechanistic study verified that elaiophylin reduced Nrf2 deacetylation, expression, and transcriptional activity as well as cytoplasm translocation by downregulating SIRT1 expression and deacetylase activity. Additionally, SIRT1/Nrf2 activation could attenuate elaiophylin-induced mitophagy inhibition and oxidative stress. The in vivo study in the A549-xenograft mice model showed that the anti-tumor effect of elaiophylin was accompanied by the decreased expressions of SIRT1, Nrf2, Parkin, and PINK1. Thus, the present study reports that elaiophylin has potent anti-tumor properties in LADC, which effect is likely mediated through suppressing the SIRT1/Nrf2 signaling. In conclusion, elaiophylin may be a novel drug candidate for LADC and SIRT1 may be a new therapeutic target for such devastating malignancy.

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Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling

Cited by 10 publications

References 57 publications

Erdafitinib Inhibits Tumorigenesis of Human Lung Adenocarcinoma A549 by Inducing S-Phase Cell-Cycle Arrest as a CDK2 Inhibitor

Erdafitinib Inhibits Tumorigenesis of Human Lung Adenocarcinoma A549 by Inducing S-Phase Cell-Cycle Arrest as a CDK2 Inhibitor

Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells

Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling

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