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

SIMPLE SUMMARY: Lung adenocarcinoma (LADC) is the pathological type with the highest morbidity and mortality among lung cancers. Although achievements in new therapeutic approaches have been developed, chemotherapy is still the most widely choice for control of LADC. However, the increasing drug res...

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Autores principales: Ji, Jiali, Wang, Ke, Meng, Xinmin, Zhong, Hongqin, Li, Xiyue, Zhao, Hongqing, Xie, Guijuan, Xie, Yunying, Wang, Xun, Zhu, Xue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737501/
https://www.ncbi.nlm.nih.gov/pubmed/36497294
http://dx.doi.org/10.3390/cancers14235812
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author Ji, Jiali
Wang, Ke
Meng, Xinmin
Zhong, Hongqin
Li, Xiyue
Zhao, Hongqing
Xie, Guijuan
Xie, Yunying
Wang, Xun
Zhu, Xue
author_facet Ji, Jiali
Wang, Ke
Meng, Xinmin
Zhong, Hongqin
Li, Xiyue
Zhao, Hongqing
Xie, Guijuan
Xie, Yunying
Wang, Xun
Zhu, Xue
author_sort Ji, Jiali
collection PubMed
description SIMPLE SUMMARY: Lung adenocarcinoma (LADC) is the pathological type with the highest morbidity and mortality among lung cancers. Although achievements in new therapeutic approaches have been developed, chemotherapy is still the most widely choice for control of LADC. However, the increasing drug resistance becomes the major challenge, so the development of the novel and efficient chemotherapeutic drug is still urgent. Elaiophylin, a new type of autophagy inhibitor, has been shown to possess unique anti-cancer activity. In this study, we have deeply investigated the therapeutic effect of elaiophylin on LADC and found elaiophylin exerts its anti-cancer effect though inhibiting mitophagy and oxidative stress and targeting SIRT1/Nrf2 signaling. This innovative and comprehensive research may provide the possibility for the development of novel chemotherapy drug for LADC. ABSTRACT: 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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spelling pubmed-97375012022-12-11 Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling Ji, Jiali Wang, Ke Meng, Xinmin Zhong, Hongqin Li, Xiyue Zhao, Hongqing Xie, Guijuan Xie, Yunying Wang, Xun Zhu, Xue Cancers (Basel) Article SIMPLE SUMMARY: Lung adenocarcinoma (LADC) is the pathological type with the highest morbidity and mortality among lung cancers. Although achievements in new therapeutic approaches have been developed, chemotherapy is still the most widely choice for control of LADC. However, the increasing drug resistance becomes the major challenge, so the development of the novel and efficient chemotherapeutic drug is still urgent. Elaiophylin, a new type of autophagy inhibitor, has been shown to possess unique anti-cancer activity. In this study, we have deeply investigated the therapeutic effect of elaiophylin on LADC and found elaiophylin exerts its anti-cancer effect though inhibiting mitophagy and oxidative stress and targeting SIRT1/Nrf2 signaling. This innovative and comprehensive research may provide the possibility for the development of novel chemotherapy drug for LADC. ABSTRACT: 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. MDPI 2022-11-25 /pmc/articles/PMC9737501/ /pubmed/36497294 http://dx.doi.org/10.3390/cancers14235812 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ji, Jiali
Wang, Ke
Meng, Xinmin
Zhong, Hongqin
Li, Xiyue
Zhao, Hongqing
Xie, Guijuan
Xie, Yunying
Wang, Xun
Zhu, Xue
Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling
title Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling
title_full Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling
title_fullStr Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling
title_full_unstemmed Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling
title_short Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling
title_sort elaiophylin inhibits tumorigenesis of human lung adenocarcinoma by inhibiting mitophagy via suppression of sirt1/nrf2 signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737501/
https://www.ncbi.nlm.nih.gov/pubmed/36497294
http://dx.doi.org/10.3390/cancers14235812
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