Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification

Abstract

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.

Knockdown of AKR1C3 Promoted Sorafenib Sensitivity Through Inhibiting the Phosphorylation of AKT in Hepatocellular Carcinoma

“…Previous studies have shown that AKR1C3 promoted tumor proliferation and may be correlated with the phosphorylation of AKT ( 20 , 21 ). We found that the mRNA level of AKT was upregulated obviously in sorafenib-resistant patients compared with sorafenib-sensitive patients ( Figure 6A ).…”

“…The activation of the AKT signal was often shown to be related to the treatment outcome, and it has been observed that it leads to resistance to chemotherapy and radiation therapy ( 36 , 37 ). AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in esophageal adenocarcinoma (EAC) cells ( 20 ). The intracellular ROS levels were induced by cadmium treatment.…”

Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death

“…The antitumor activity of cisplatin is a complex process in which several pathways are involved, leading to cell cycle arrest, apoptosis, ferroptosis, and autophagy, depending on the treatment conditions and the cell type [26][27][28]. Cisplatin-induced cell death via apoptosis is the predominant pathway.…”

“…This indicates that cisplatin could induce ROS generation in KATO cells in a way that was dependent upon the activity of AKR1C1 and 1C3. Nrf2 is a transcriptional factor that is activated by modification of Cys thiols in Keap1 in response to activators such as ROS, electrophiles, and nitrogen radicals [28,36]. Moreover, a previously published report stated that AKR1C3 is said to be a direct target of Nrf2 and plays an essential role in redox balance.…”

Comparative Analysis of Coumarin Profiles in Different Parts of Peucedanum japonicum and Their Aldo–Keto Reductase Inhibitory Activities

“…In addition, AKR1C1 is associated with cisplatin-resistance in colon cancer cell, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, and paediatric T-cell acute lymphoblastic leukemia [ 30 , 31 , 32 , 33 ]. It has been recently reported that AKR1C3 mediates chemotherapy resistance in breast cancer and esophageal adenocarcinoma [ 34 , 35 ]. Thus, AKR1C isoforms may be a potential target for preventing the development of anticancer drug resistance.…”