title: The roles of AKR1C1 and AKR1C2 in ethyl-3,4-dihydroxybenzoate induced esophageal squamous cell carcinoma cell death.
abstract: The aldo-keto reductase (AKR) superfamily of enzymes is critical for the detoxification of drugs and toxins in the human body; these enzymes are involved not only in the development of drug resistance in cancer cells but also in the metabolism of polycyclic aromatic hydrocarbons. Here, we demonstrated that AKR1C1/C2 increased the metabolism of ethyl-3,4-dihydroxybenzoate (EDHB) in esophageal squamous cell carcinoma (ESCC) cells. Previous studies have shown that EDHB can effectively induce esophageal cancer cell autophagy and apoptosis, and the AKR1C family represents one set of highly expressed genes after EDHB treatment. To explore the cytotoxic effects of EDHB, esophageal cancer cells with higher (KYSE180) or lower (KYSE510) AKR1C expression levels were evaluated in this study. The proliferation of KYSE180 cells was inhibited more effectively than that of KYSE510 cells by EDHB treatment. Furthermore, the effective subunits of the AKR superfamily, AKR1C1/C2, were quantitatively identified using multiple reaction monitoring (MRM) assays. The sensitivity of esophageal cancer cells to EDHB was significantly attenuated by the siRNA knockdown of AKR1C1/C2. Moreover, the expression of autophagy inducers (Beclin, LC3II and BNIP3) and NDRG1 was significantly elevated in KYSE180 cells, but not in KYSE510 cells, after EDHB treatment. When autophagy was inhibited by 3-methyladenine, KYSE180 cells exhibited an increased sensitivity to EDHB, which may be a metabolic substrate of AKR1C1/C2. These results indicated that ESCC patients with high AKR1C1/C2 expression may be more sensitive to EDHB, and AKR1C1/C2 may facilitate EDHB-induced autophagy and apoptosis, thus providing potential guidance for the chemoprevention of ESCC.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.|Proteomics Division, BGI-Shenzhen, Shenzhen, Guangdong, China.
authors.forename: Guixue
authors.initials: G
authors.lastname: Hou
authors.affiliation: Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
authors.forename: Dianrong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Lou
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.|Proteomics Division, BGI-Shenzhen, Shenzhen, Guangdong, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Zhao
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D062385:Hydroxybenzoates / Q000378:metabolism / Q000494:pharmacology*; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D015089:20-Hydroxysteroid Dehydrogenases; D062385:Hydroxybenzoates; D006913:Hydroxysteroid Dehydrogenases; C018063:ethyl protocatechuate; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
keywords: 4-dihydroxybenzoate; ESCC; MRM; aldo-keto reductase 1C1/C2; ethyl-3