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.

Role of aquaporins in cell proliferation: What else beyond water permeability?

“…16,[97][98][99][100] For instance, expression of AQP5 is positively correlated with drug resistance factors, and silencing of AQP5 inhibits the cell proliferation at the same time that diminishes the phosphorylation of MAPK p38. 99 In skin, AQP3 is important for the phosphorylation of p38, ERK and JNK in keratinocyte, and less phosphorylation of p38 and JNK was observed in epidermis from AQP3-null mice which exhibit clearly impaired wound healing capacity compared to wild-type animals.…”

“…16,[97][98][99][100] For instance, expression of AQP5 is positively correlated with drug resistance factors, and silencing of AQP5 inhibits the cell proliferation at the same time that diminishes the phosphorylation of MAPK p38. 99 In skin, AQP3 is important for the phosphorylation of p38, ERK and JNK in keratinocyte, and less phosphorylation of p38 and JNK was observed in epidermis from AQP3-null mice which exhibit clearly impaired wound healing capacity compared to wild-type animals. 14 Further, the activation of GSK-3b, ERK, JNK, and p38 MAPK pathways has been associated with levels of AQP2 and proliferation in kidney collecting duct cells treated with lithium; 101,102 while the antiproliferative and anti-metastasis activity of anti-prostate cancer compounds such as Rg3 was associated with p38 MAPK-mediated downregulation of AQP1.…”

The emerging role of aquaporin 5 (AQP5) expression in systemic malignancies

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To the editor,We read with great interest the recent article entitled "AQP5 silencing suppresses p38 MAPK signaling and improves drug resistance in colon cancer cells" published in Tumor Biology, identifying that aquaporin 5 (AQP5) can participate in mediating colon cancer pathogenesis and drug resistance as well as recurrence in colon cancer [1]. To date, AQP5, ubiquitously found in mammalian cells such as mammary gland, is a membrane of transmembrane proteins that play significant roles in water and small solute transport across epithelial and endothelial barriers [2].

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“…To date, AQP5, ubiquitously found in mammalian cells such as mammary gland, is a membrane of transmembrane proteins that play significant roles in water and small solute transport across epithelial and endothelial barriers [2]. Interestingly, emerging data suggests that AQP5 expression may participate in the growth and progression of a number of systemic malignancies besides colon cancer [1].In mammary malignancies, for instance, Lee et al [3] in a recent study of AQP5 expression in individuals with early breast cancer (EBC) reports that nearly 60 % of the patients were immune-positive for AQP5. Simultaneously, AQP5 overexpression was significantly connected with survival for the patients with estrogen receptor/progesterone receptorpositive and human epidermal growth factor receptor 2-overexpressed EBC.…”

“…To date, AQP5, ubiquitously found in mammalian cells such as mammary gland, is a membrane of transmembrane proteins that play significant roles in water and small solute transport across epithelial and endothelial barriers [2]. Interestingly, emerging data suggests that AQP5 expression may participate in the growth and progression of a number of systemic malignancies besides colon cancer [1].…”