Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling
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-...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2022-11-01
|
Series: | Cancers |
Subjects: | |
Online Access: | https://www.mdpi.com/2072-6694/14/23/5812 |
_version_ | 1797463546966048768 |
---|---|
author | Jiali Ji Ke Wang Xinmin Meng Hongqin Zhong Xiyue Li Hongqing Zhao Guijuan Xie Yunying Xie Xun Wang Xue Zhu |
author_facet | Jiali Ji Ke Wang Xinmin Meng Hongqin Zhong Xiyue Li Hongqing Zhao Guijuan Xie Yunying Xie Xun Wang Xue Zhu |
author_sort | Jiali Ji |
collection | DOAJ |
description | 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. |
first_indexed | 2024-03-09T17:52:17Z |
format | Article |
id | doaj.art-6519b52fd3a24d67a2de8b97a8b7e03f |
institution | Directory Open Access Journal |
issn | 2072-6694 |
language | English |
last_indexed | 2024-03-09T17:52:17Z |
publishDate | 2022-11-01 |
publisher | MDPI AG |
record_format | Article |
series | Cancers |
spelling | doaj.art-6519b52fd3a24d67a2de8b97a8b7e03f2023-11-24T10:39:05ZengMDPI AGCancers2072-66942022-11-011423581210.3390/cancers14235812Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 SignalingJiali Ji0Ke Wang1Xinmin Meng2Hongqin Zhong3Xiyue Li4Hongqing Zhao5Guijuan Xie6Yunying Xie7Xun Wang8Xue Zhu9Department of Respiratory and Critical Care Medicine, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi 214002, ChinaNational Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, ChinaDepartment of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Nanning 530021, ChinaDepartment of Respiratory and Critical Care Medicine, Wuxi Clinical College Affiliated to Nantong University, Wuxi 214002, ChinaDepartment of Respiratory and Critical Care Medicine, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi 214002, ChinaDepartment of Respiratory and Critical Care Medicine, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi 214002, ChinaDepartment of Respiratory and Critical Care Medicine, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi 214002, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaDepartment of Respiratory and Critical Care Medicine, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi 214002, ChinaNational Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, ChinaLung 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.https://www.mdpi.com/2072-6694/14/23/5812lung adenocarcinomaelaiophylinmitophagyoxidative stressSIRT1/Nrf2 signaling |
spellingShingle | Jiali Ji Ke Wang Xinmin Meng Hongqin Zhong Xiyue Li Hongqing Zhao Guijuan Xie Yunying Xie Xun Wang Xue Zhu Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling Cancers lung adenocarcinoma elaiophylin mitophagy oxidative stress 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 | lung adenocarcinoma elaiophylin mitophagy oxidative stress SIRT1/Nrf2 signaling |
url | https://www.mdpi.com/2072-6694/14/23/5812 |
work_keys_str_mv | AT jialiji elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT kewang elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT xinminmeng elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT hongqinzhong elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT xiyueli elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT hongqingzhao elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT guijuanxie elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT yunyingxie elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT xunwang elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling AT xuezhu elaiophylininhibitstumorigenesisofhumanlungadenocarcinomabyinhibitingmitophagyviasuppressionofsirt1nrf2signaling |