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环磷酸腺苷（cAMP）在胰腺腺癌细胞系中对多药耐药相关蛋白4（MRP4）转录调控的双重作用

Dual role of cAMP in the transcriptional regulation of multidrug resistance-associated protein 4 (MRP4) in pancreatic adenocarcinoma cell lines.

作者信息

Carozzo Alejandro, Diez Federico, Gomez Natalia, Cabrera Maia, Shayo Carina, Davio Carlos, Fernández Natalia

机构信息

Laboratorio de Farmacología de Receptores, Cátedra de Química Medicinal, Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.

Laboratorio de Farmacología de Receptores, Cátedra de Química Medicinal, Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina; Laboratorio de Patología y Farmacología Molecular, Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina.

出版信息

PLoS One. 2015 Mar 19;10(3):e0120651. doi: 10.1371/journal.pone.0120651. eCollection 2015.

DOI:10.1371/journal.pone.0120651
PMID:25790437
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4366062/
Abstract

Cyclic AMP represents one of the most studied signaling molecules and its role in proliferation and differentiation processes has been well established. Intracellular cAMP levels are tightly regulated where the MRP4 transporter plays a major role. In the present study, we sought to establish whether cAMP modulated MRP4 expression in pancreatic adenocarcinoma cell lines. Quantitative PCR and western blot studies showed that cAMP-increasing agents enhanced MRP4 transcripts and protein levels in PANC-1 cells. Reporter luciferase experiments carried out in pancreatic AR42J cells showed that intracellular cAMP up-regulates MRP4 through an Epac2- and Rap1-mediated mechanism whereas extracellular cAMP reduced MRP4 promoter activity by a MEK/ERK-mediated pathway. Present results show that cAMP regulates MRP4 promoter activity, and further indicate that the balance between intracellular and extracellular cAMP levels determines MRP4 expression.

摘要

环磷酸腺苷（cAMP）是研究最为深入的信号分子之一，其在增殖和分化过程中的作用已得到充分证实。细胞内cAMP水平受到严格调控，其中多药耐药相关蛋白4（MRP4）转运体发挥着主要作用。在本研究中，我们试图确定cAMP是否调节胰腺腺癌细胞系中MRP4的表达。定量PCR和蛋白质印迹研究表明，提高cAMP的试剂可增强PANC-1细胞中MRP4的转录本和蛋白质水平。在胰腺AR42J细胞中进行的荧光素酶报告基因实验表明，细胞内cAMP通过Epac2和Rap1介导的机制上调MRP4，而细胞外cAMP通过MEK/ERK介导的途径降低MRP4启动子活性。目前的结果表明，cAMP调节MRP4启动子活性，并进一步表明细胞内和细胞外cAMP水平之间的平衡决定了MRP4的表达。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/d8eaea84e491/pone.0120651.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/c9b2d00067b9/pone.0120651.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/104ba08f7a59/pone.0120651.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/a72036b39e9e/pone.0120651.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/11e446ce9d8f/pone.0120651.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/b126ce657cfc/pone.0120651.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/6ba417c87f08/pone.0120651.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/d8eaea84e491/pone.0120651.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/c9b2d00067b9/pone.0120651.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/104ba08f7a59/pone.0120651.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/a72036b39e9e/pone.0120651.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/11e446ce9d8f/pone.0120651.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/b126ce657cfc/pone.0120651.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/6ba417c87f08/pone.0120651.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6614/4366062/d8eaea84e491/pone.0120651.g007.jpg

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