Xu Minqin, Zhang Lihua, Lin Lan, Qiang Zhiyi, Liu Wei, Yang Jian
Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
J Biomed Res. 2023 Nov 15;37(6):431-447. doi: 10.7555/JBR.37.20230047.
-Diamminedichloroplatinum (CDDP) is widely used for the treatment of various solid cancers. Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2), along with the upregulation of pregnane X receptor (PXR) and the downregulation of differentiated embryonic chondrocyte-expressed gene 1 (DEC1) in human hepatoma cells, primary mouse hepatocytes, mouse liver and intestine. The overexpression or knockdown of PXR alone upregulated or downregulated the CES1 and CES2 expression, respectively. The increases in CES1 and CES2 expression levels induced by CDDP abolished or enhanced by PXR knockdown or overexpression, implying that CDDP induces carboxylesterases through the activation of PXR. Likewise, the overexpression or knockdown of DEC1 alone significantly decreased or increased PXR and its targets. Moreover, the increases of PXR and its targets induced by CDDP were abolished or alleviated by the overexpression or knockdown of DEC1. The overexpression or knockdown of DEC1 affected the response of PXR to CDDP, but not vice versa, suggesting that CDDP increases carboxylesterases by upregulating PXR mediated by the decrease of DEC1. In addition, CDDP did not increase mRNA degradation but suppressed DEC1 promoter reporter activity, indicating that it suppresses DEC1 transcriptionally. The combined use of CDDP and irinotecan had a synergistic effect on two cell lines, especially when CDDP was used first.
顺二氯二氨合铂（CDDP）被广泛用于治疗各种实体癌。在此我们报告，在人肝癌细胞、原代小鼠肝细胞、小鼠肝脏和肠道中，CDDP增加了羧酸酯酶1（CES1）和羧酸酯酶2（CES2）的表达及酶活性，同时上调了孕烷X受体（PXR）并下调了分化胚胎软骨细胞表达基因1（DEC1）。单独过表达或敲低PXR分别上调或下调了CES1和CES2的表达。CDDP诱导的CES1和CES2表达水平的增加分别被PXR敲低或过表达所消除或增强，这意味着CDDP通过激活PXR诱导羧酸酯酶。同样，单独过表达或敲低DEC1分别显著降低或增加了PXR及其靶标。此外，CDDP诱导的PXR及其靶标的增加分别被DEC1的过表达或敲低所消除或减轻。DEC1的过表达或敲低影响了PXR对CDDP的反应，但反之则不然，这表明CDDP通过由DEC1降低介导的PXR上调来增加羧酸酯酶。此外，CDDP并未增加mRNA降解，但抑制了DEC1启动子报告基因活性，表明它在转录水平上抑制DEC1。CDDP与伊立替康联合使用对两种细胞系具有协同作用，尤其是当首先使用CDDP时。
