The roles of AKR1C1 and AKR1C2 in ethyl-3,4-dihydroxybenzoate induced esophageal squamous cell carcinoma cell death.
The roles of AKR1C1 and AKR1C2 in ethyl-3,4-dihydroxybenzoate induced esophageal squamous cell carcinoma cell death.
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DOI：
10.18632/oncotarget.7775
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发表时间：
2016-04-19
期刊：
影响因子：
--
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Li W;Hou G;Zhou D;Lou X;Xu Y;Liu S;Zhao X
醛酮还原酶（AKR）超家族对人体药物和毒素的解毒至关重要；这些酶不仅参与了癌细胞耐药的发展，而且还参与了多环芳烃的代谢。在这里，我们证明AKR1C1/C2增加了食管鳞状细胞癌（ESCC）细胞中乙基-3,4-二羟基苯甲酸酯（EDHB）的代谢。既往研究表明，EDHB能有效诱导食管癌细胞自噬和凋亡，而AKR1C家族是EDHB治疗后高表达的一组基因。为了探索EDHB的细胞毒性作用，本研究对AKR1C表达水平较高（KYSE180）或较低（KYSE510）的食管癌细胞进行了评估。EDHB对KYSE180细胞的增殖抑制作用强于KYSE510细胞。此外，AKR超家族的有效亚基AKR1C1/C2通过多重反应监测（MRM）定量鉴定。通过敲低AKR1C1/C2的siRNA，食管癌细胞对EDHB的敏感性显著降低。此外，EDHB处理后，KYSE180细胞中自噬诱导剂（Beclin、LC3II和BNIP3）和NDRG1的表达显著升高，而KYSE510细胞中则没有。当自噬被3-甲基腺嘌呤抑制时，KYSE180细胞对EDHB的敏感性增加，EDHB可能是AKR1C1/C2的代谢底物。这些结果提示AKR1C1/C2高表达的ESCC患者可能对EDHB更敏感，AKR1C1/C2可能促进EDHB诱导的自噬和凋亡，从而为ESCC的化学预防提供潜在的指导。
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.
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脯氨酰羟化酶抑制剂 3,4-二羟基苯甲酸乙酯通过上调 BNIP3 和 N-myc 下游调节基因 1 诱导食管鳞状细胞癌细胞自噬和凋亡
影响因子：
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作者：
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DOI：
10.1016/j.jsbmb.2009.12.009
发表时间：
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影响因子：
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作者：
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