title: AQP5 silencing suppresses p38 MAPK signaling and improves drug resistance in colon cancer cells.
abstract: It is known that aquaporin 5 (AQP5) may represent a novel therapeutic target for treating colon cancer (CC), but whether AQP5 plays a role in the regulation of multidrug resistance (MDR) of colon cancer still remains unclear. In the present study, AQP5 and P-glycoprotein (P-gp), glutathione S-transferase-π (GST-π), topoisomerase II (TOPO II), and thymidylate synthase (TS) were checked in CC and adjacent cancer tissues; AQP5-siRNA was applied to silencing AQP5 in CC cell line HT-29, 5-fluorouracil (5-FU), and cisplatin (DDP) added on cells, and sulforhodamine B (SRB) was used; fluorescence real-time quantitative RT-PCR and Western blot were employed to detect changes in multidrug resistance factor and expression mitogen-activated protein kinase (MAPK) signaling pathway in HT-29. The results showed that AQP5 is significantly induced in cancer tissues than that in adjacent cancer tissues. The expression of AQP5 is positively correlated with drug resistance factors, as demonstrated by the increased expressions of P-gp, GST-π, and TOPO II in CC tissues compared to that in adjacent cancer tissues. Conversely, knockdown of AQP5 in HT-29 human colon cancer cells increased inhibition rates of cancer chemotherapeutic drugs such as 5-FU and DDP. The improved efficacies of chemotherapeutic drugs are associated with the decreased expression of P-gp, GST-π, and TOPO II. In addition, phosphorylation of p38 MAPK was increased by knockdown of AQP5 in HT-29 cells while phosphorylation and expression of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and Protein kinase B (AKT) were not affected. P38 MAPK inhibitor increased the drug sensitivity of HT-29 cells in a similar way as AQP5-siRNAs do. So these results indicate that AQP5 is associated with drug resistance of colon cancer, and that the AQP5-P38 MAPK pathway may represent a potential drug target to improve drug resistance of colon cancer cells.
authors.affiliation: Department of General Surgery, Hebei General Hospital, Hebei, Shijiazhuang, 050051, China, shixiaoming2013@126.com.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Shi
authors.forename: Shengchun
authors.initials: S
authors.lastname: Wu
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Yang
authors.forename: Lei
authors.initials: L
authors.lastname: Tang
authors.forename: Yüexin
authors.initials: Y
authors.lastname: Wang
authors.forename: Junjie
authors.initials: J
authors.lastname: Dong
authors.forename: Bonan
authors.initials: B
authors.lastname: Lü
authors.forename: Guangwei
authors.initials: G
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D051402:Aquaporin 5 / Q000235:genetics* / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006801:Humans; D027361:Organic Anion Transporters / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013940:Thymidylate Synthase / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051402:Aquaporin 5; D002945:Cisplatin; D004250:DNA Topoisomerases, Type II; D005472:Fluorouracil; D027361:Organic Anion Transporters; D013940:Thymidylate Synthase; D048051:p38 Mitogen-Activated Protein Kinases; C496036:AQP5 protein, human; C487009:SLCO6A1 protein, human
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