Universität zu Köln

Zhou, Chenghui ORCID: 0000-0003-1170-1761, Wang, Zhefang ORCID: 0000-0002-2297-2586, Li, Jiahui, Wu, Xiaolin, Fan, Ningbo ORCID: 0000-0002-1622-6747, Li, Dai, Liu, Fanyu, Plum, Patrick S. ORCID: 0000-0002-8165-4553, Hoppe, Sascha, Hillmer, Axel M., Quaas, Alexandar, Gebauer, Florian ORCID: 0000-0001-5312-4814, Chon, Seung-Hun ORCID: 0000-0002-8923-6428, Bruns, Christiane J. and Zhao, Yue ORCID: 0000-0002-6790-3402 (2021). Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification. Cancers, 13 (10). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary The multidrug resistance of EAC is one of the major obstacles to chemotherapeutic efficiency. Our study aims to explore the molecular mechanism of AKR1C3 as a novel therapeutic target to overcome chemotherapy resistance for EAC patients. We demonstrate that AKR1C3 renders chemotherapy resistance through controlling cellular ROS levels via AKT signaling in EAC cells. Modulation of intracellular GSH levels by AKR1C3 could scavenge the intracellular ROS, thus regulating apoptosis. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy treatment and benefit the overall survival of patients diagnosed with EAC. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Zhou, Chenghui UNSPECIFIED orcid.org/0000-0003-1170-1761 UNSPECIFIED Wang, Zhefang UNSPECIFIED orcid.org/0000-0002-2297-2586 UNSPECIFIED Li, Jiahui UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Xiaolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Fan, Ningbo UNSPECIFIED orcid.org/0000-0002-1622-6747 UNSPECIFIED Li, Dai UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Fanyu UNSPECIFIED UNSPECIFIED UNSPECIFIED Plum, Patrick S. UNSPECIFIED orcid.org/0000-0002-8165-4553 UNSPECIFIED Hoppe, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Hillmer, Axel M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Quaas, Alexandar UNSPECIFIED UNSPECIFIED UNSPECIFIED Gebauer, Florian UNSPECIFIED orcid.org/0000-0001-5312-4814 UNSPECIFIED Chon, Seung-Hun UNSPECIFIED orcid.org/0000-0002-8923-6428 UNSPECIFIED Bruns, Christiane J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Yue UNSPECIFIED orcid.org/0000-0002-6790-3402 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-591017
DOI:	10.3390/cancers13102403
Journal or Publication Title:	Cancers
Volume:	13
Number:	10
Date:	2021
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language OVARIAN-CANCER CELLS; CISPLATIN-RESISTANCE; OXIDATIVE STRESS; CARCINOMA-CELLS; AKR1C3; AKT; APOPTOSIS; CHEMORESISTANCE; TUMORIGENESIS; ANTIOXIDANT Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59101