Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification
Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that t...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-05-01
|
Series: | Cancers |
Subjects: | |
Online Access: | https://www.mdpi.com/2072-6694/13/10/2403 |
id |
doaj-050d9b53cba741898dfc83cf24da0ac1 |
---|---|
record_format |
Article |
spelling |
doaj-050d9b53cba741898dfc83cf24da0ac12021-06-01T00:11:04ZengMDPI AGCancers2072-66942021-05-01132403240310.3390/cancers13102403Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS DetoxificationChenghui Zhou0Zhefang Wang1Jiahui Li2Xiaolin Wu3Ningbo Fan4Dai Li5Fanyu Liu6Patrick S. Plum7Sascha Hoppe8Axel M. Hillmer9Alexandar Quaas10Florian Gebauer11Seung-Hun Chon12Christiane J. Bruns13Yue Zhao14Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyFaculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, 50937 Cologne, GermanyFaculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, 50937 Cologne, GermanyFaculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyDepartment of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, GermanyEsophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.https://www.mdpi.com/2072-6694/13/10/2403esophageal adenocarcinomaAKR1C3chemotherapy resistanceAKT signalingROS regulationprognosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chenghui Zhou Zhefang Wang Jiahui Li Xiaolin Wu Ningbo Fan Dai Li Fanyu Liu Patrick S. Plum Sascha Hoppe Axel M. Hillmer Alexandar Quaas Florian Gebauer Seung-Hun Chon Christiane J. Bruns Yue Zhao |
spellingShingle |
Chenghui Zhou Zhefang Wang Jiahui Li Xiaolin Wu Ningbo Fan Dai Li Fanyu Liu Patrick S. Plum Sascha Hoppe Axel M. Hillmer Alexandar Quaas Florian Gebauer Seung-Hun Chon Christiane J. Bruns Yue Zhao Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification Cancers esophageal adenocarcinoma AKR1C3 chemotherapy resistance AKT signaling ROS regulation prognosis |
author_facet |
Chenghui Zhou Zhefang Wang Jiahui Li Xiaolin Wu Ningbo Fan Dai Li Fanyu Liu Patrick S. Plum Sascha Hoppe Axel M. Hillmer Alexandar Quaas Florian Gebauer Seung-Hun Chon Christiane J. Bruns Yue Zhao |
author_sort |
Chenghui Zhou |
title |
Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification |
title_short |
Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification |
title_full |
Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification |
title_fullStr |
Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification |
title_full_unstemmed |
Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification |
title_sort |
aldo-keto reductase 1c3 mediates chemotherapy resistance in esophageal adenocarcinoma via ros detoxification |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-05-01 |
description |
Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy. |
topic |
esophageal adenocarcinoma AKR1C3 chemotherapy resistance AKT signaling ROS regulation prognosis |
url |
https://www.mdpi.com/2072-6694/13/10/2403 |
work_keys_str_mv |
AT chenghuizhou aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT zhefangwang aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT jiahuili aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT xiaolinwu aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT ningbofan aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT daili aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT fanyuliu aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT patricksplum aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT saschahoppe aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT axelmhillmer aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT alexandarquaas aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT floriangebauer aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT seunghunchon aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT christianejbruns aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification AT yuezhao aldoketoreductase1c3mediateschemotherapyresistanceinesophagealadenocarcinomaviarosdetoxification |
_version_ |
1721415511726620672 |