title: Multidrug Resistance-Associated Protein 2 Expression Is Upregulated by Adenosine 5'-Triphosphate in Colorectal Cancer Cells and Enhances Their Survival to Chemotherapeutic Drugs.
abstract: Extracellular adenosine 5'-triphosphate (ATP) is a signaling molecule that induces a plethora of effects ranging from the regulation of cell proliferation to modulation of cancerous cell behavior. In colorectal cancer, ATP was reported to stimulate epithelial cell proliferation and possibly promote resistance to anti-cancer treatments. However, the exact role of this danger-signaling molecule on cancerous intestinal epithelial cells (IECs) in response to chemotherapeutic agents remains unknown. To address how ATP may influence the response of cancerous IECs to chemotherapeutic agents, we used Caco-2 cells, which display enterocyte-like features, to determine the effect of ATP on the expression of multidrug resistance-associated protein 2 (MRP2). Gene and protein expression were determined by quantitative real-time PCR (qRT-PCR) and Western blotting. Resistance to etoposide, cisplatin and doxorubicin was determined by MTT assays in response to ATP stimulation of Caco-2 cells and in cells for which MRP2 expression was down-regulated by shRNA. ATP increased the expression of MRP2 at both the mRNA and protein levels. MRP2 expression involved an ATP-dependent stimulation of the MEK/ERK signaling pathway that was associated with an increase in relative resistance of Caco-2 cells to etoposide. Abolition of MRP2 expression using shRNA significantly reduced the protective effect of MRP2 toward etoposide as well as to cisplatin and doxorubicin. This study describes the mechanism by which ATP may contribute to the chemoresistance of cancerous IECs in colorectal cancer. Given the heterogeneity of colorectal adenocarcinoma responses to anti-cancer drugs, these findings call for further study to understand the role of P2 receptors in cancer drug therapy and to develop novel therapies aimed at regulating P2 receptor activity.
authors: Department of Anatomy and Cell Biology, Faculté de Médecine et des Sciences de la Santé, Pavillon de Recherche Appliquée sur le Cancer, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Valérie
authors: V
authors: Vinette
authors: Department of Anatomy and Cell Biology, Faculté de Médecine et des Sciences de la Santé, Pavillon de Recherche Appliquée sur le Cancer, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Morgane
authors: M
authors: Placet
authors: Department of Anatomy and Cell Biology, Faculté de Médecine et des Sciences de la Santé, Pavillon de Recherche Appliquée sur le Cancer, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Guillaume
authors: G
authors: Arguin
authors: Department of Anatomy and Cell Biology, Faculté de Médecine et des Sciences de la Santé, Pavillon de Recherche Appliquée sur le Cancer, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Fernand-Pierre
authors: FP
authors: Gendron
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D002945:Cisplatin; D004317:Doxorubicin; D005047:Etoposide; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D034741:RNA, Small Interfering; D058470:Receptors, Purinergic P2Y; C000715087:ABCC2 protein, human