Omeprazole Inhibits Pancreatic Cancer Cell Invasion through a Nongenomic Aryl Hydrocarbon Receptor Pathway.
Omeprazole Inhibits Pancreatic Cancer Cell Invasion through a Nongenomic Aryl Hydrocarbon Receptor Pathway.
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DOI：
10.1021/tx5005198
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发表时间：
2015-05-18
影响因子：
4.1
通讯作者：
Safe S
中科院分区：
文献类型：
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作者：
Jin UH;Kim SB;Safe S
奥美拉唑和2,3,7,8 - 四氯二苯并 - 对 - 二噁英（TCDD）是芳香烃受体（AhR）激动剂，它们通过抑制CXCR4转录来抑制乳腺癌细胞的侵袭。用TCDD、奥美拉唑和其他七种具有AhR活性的药物处理高侵袭性的Panc1胰腺癌细胞，结果表明在博伊登小室实验中只有奥美拉唑和曲尼司特而非TCDD抑制侵袭。在另一种准间质胰腺导管腺癌（QM - PDA）胰腺癌细胞系MiaPaCa2细胞中也观察到了类似结果，然而在被归类为“经典型”（侵袭性较弱）的胰腺癌细胞BxPC3或L3.6pL细胞中未观察到侵袭现象。还观察到在QM - PDA细胞中，TCDD、奥美拉唑和曲尼司特不会诱导CYP1A1或CXCR4，并且用这些化合物处理不会导致AhR的核摄取。相比之下，用这些AhR配体处理BxPC3和L3.6pL细胞会导致CYP1A1的诱导（由TCDD引起）以及AhR的核摄取，这与在对Ah有反应的MDA - MB - 468乳腺癌和HepG2肝癌细胞系中观察到的情况相似。在Panc1和MiaPaCa2细胞中进行的AhR和AhR核转运蛋白（Arnt）敲低实验结果表明，奥美拉唑和曲尼司特介导的侵袭抑制是依赖AhR但不依赖Arnt的。这些结果表明，在侵袭性最强的胰腺癌细胞亚型（QM - PDA）中，选择性AhR调节剂奥美拉唑和曲尼司特通过一种非基因组的AhR途径抑制侵袭。
Omeprazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are aryl hydrocarbon receptor (AhR) agonist that inhibit invasion of breast cancer cell through inhibition of CXCR4 transcription. Treatment of highly invasive Panc1 pancreatic cancer cells with TCDD, omeprazole and seven other AhR-active pharmaceuticals showed that only omeprazole and tranilast but not TCDD inhibited invasion in a Boyden chamber assay. Similar results were observed in MiaPaCa2 cells, another quasimensenchymal pancreatic ductal adenocarcinoma (QM-PDA) pancreatic cancer cell line, whereas invasion was not observed in BxPC3 or L3.6pL cells which are classified as “classical” (less invasive) pancreatic cancer cells. It was also observed that in the QM-PDA cells that TCDD, omeprazole and tranilast did not induce CYP1A1 or CXCR4 and treatment with these compounds did not result in nuclear uptake of the AhR. In contrast, treatment of BxPC3 and L3.6pL cells with these AhR ligands resulted in induction of CYP1A1 (by TCDD) and nuclear uptake of the AhR which was similar to that observed for Ah-responsive MDA-MB-468 breast and HepG2 liver cancer cell lines. Results of AhR and AhR nuclear translocator (Arnt) knockdown experiments in Panc1 and MiaPaCa2 cells demonstrate that omeprazole- and tranilast-mediated inhibition of invasion was AhR-dependent but Arnt-independent. These results demonstrate that in the most highly invasive sub-type of pancreatic cancer cells (QM-PDA), the selective AhR modulators omeprazole and tranilast inhibit invasion through a non-genomic AhR pathway.