Methyl jasmonate enhances the radiation sensitivity of esophageal carcinoma cells by inhibiting the 11-ketoprostaglandin reductase activity of <em>AKR1C3</em>

Abstract

PurposeIn our previous study, we found that AKR1C3 was a radioresistance gene in KY170R cells. Downregulating the expression of AKR1C3 could enhance the radiosensitivity of esophageal carcinoma cells. In this study, we investigated whether methyl jasmonate (MeJ), an inhibitor of Aldo-keto reductase family1 member C3 (AKR1C3), could overcome radiation resistance in AKR1C3 highly expressed cells.Patients and methodsWe used clone formation assays to detect radiosensitivity effects. Flow cytometry assays were used to detect reactive oxygen species (ROS) accumulation and apoptosis. Enzyme linked immunosorbent assays (ELISAs) were used to detect the concentrations of prostaglandin F2 (PGF2) and prostaglandin D2 (PGD2) in the cells after incubation with MeJ. Western blotting was used to detect AKR1C3 and peroxisome proliferator-activated receptor gamma (PPARγ) expression.ResultsWe found that AKR1C3 was highly expressed in radioresistant esophageal carcinoma cells. MeJ inhibited the expression of AKR1C3 and enhanced the radiation sensitivity of esophageal carcinoma cells expressing high levels of AKR1C3 (P<0.05). MeJ could inhibit the 11-ketoprostaglandin reductase activity of AKR1C3 in a dose-dependent manner in KY170R cells. Incubation of KY170R cells with 200 µmol/L of MeJ for 24 h reduced the expression of PGF2 by roughly 30% (P<0.05). The PPAR pathway inhibitor GW9662 prevented the radiation sensitivity enhancement imparted by MeJ. After adding GW9662, there were no significant differences between the radiation sensitivities of MeJ-treated and -untreated KY170R cells (P>0.05). The radiation sensitivity effect of MeJ also depended upon the generation of ROS in KY170R cells; 48 h after irradiation, ROS levels in the MeJ group was twofold higher than in the untreated KY170R cells (P<0.05). The ROS scavenger, N-acetyl cysteine, could reverse the radiosensitivity effects of MeJ (P>0.05).ConclusionOur results indicate that MeJ can increase the radiation sensitivity of AKR1C3-overexpressing KY170R cells by inhibiting the 11-ketoprostaglandin reductase activity of AKR1C3 and increasing cellular ROS levels.

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

“…Under the selective pressure induced by chemotherapeutic drugs, cancer cells would evolve an antioxidant system to protect themselves against oxidative stress via neutralizing the over-produced intracellular ROS [ 50 , 51 ]. Although the connection of AKR1C3 with ROS regulation has already been indicated in prostate cancer and ESCC, these studies mainly focused on radiation resistance, and the underlying molecular mechanism of the regulatory role of AKR1C3 with ROS is not well investigated [ 31 , 32 ]. Surprisingly, we observed that increased expression of AKR1C3 protected EAC cells from apoptosis by scavenging the over-produced ROS.…”

“…It is also possible that AKR1C3 mediates chemotherapy resistance through the function of drug metabolism. Li et al found that inhibiting the 11-ketoprostaglandin reductase activity of AKR1C3 could enhance the radiation sensitivity in ESCC [ 32 ]. In addition, Matsunaga et al reported that AKR1C3 showed doxorubicin-reductase activity in gastrointestinal cancer cells [ 62 ].…”

“…AKR1C3 has already been implicated in therapeutic resistance via mediating intracellular ROS levels in several types of cancer, such as prostate cancer, ESCC, choriocarcinoma and leukemias [ 30 , 31 , 32 , 33 ]. AKR1C3 silencing reverses methotrexate (MTX) resistance in choriocarcinoma cells by increasing ROS levels [ 33 ].…”

Jasmonate Compounds and Their Derivatives in the Regulation of the Neoplastic Processes

“…Excessive production of ROS in cancer cells can lead to the oxidative modification of DNA and lipids, which in turn causes damage to cell membranes. Both jasmonic acid and its methyl ester cause a significant increase in ROS levels in glioblastoma cells (C6), non-small cell lung cancer cells (A549 and H520) and in uterine cancer cell lines (HeLa and CaSki) [ 28 , 45 , 46 , 47 , 48 ].…”

“…MJ also leads to an increase in the sensitivity of cells to ionizing radiation [ 50 ]. On the other hand, in esophageal squamous cell carcinoma (KY170R) cells, MJ (200 µM for 24 h) increases the level of ROS and inhibits the activity of 11-ketoprostaglandin reductase (by roughly 30%), which dramatically increases cell death in response to X-rays [ 46 ].…”