RhoGDI2 up-regulates P-glycoprotein expression via Rac1 in gastric cancer cells

Abstract

Multidrug resistance (MDR) is a major clinical obstacle in treatment of gastric cancer. Previously, using 2D electrophoresis-mass spectrometry, we identified RhoGDI2 as a contributor to 5-FU resistance in colon cancer cells, and also confer gastric cancer cells resistance to 5-FU. Here, we reported RhoGDI2 also induced MDR in gastric cancer cell line (MKN-45). To explore the underlining mechanism, we detected the mRNA, protein expression, activity of P-glycoprotein (P-gp) in MKN-45 stably transfected with RhoGDI2 expressing or control vector. All the mRNA, protein level, activity were increased by 130%, 230%, 35% respectively after ectopic expression of RhoGDI2. RhoGDI2 was correlated with P-gp expression in gastric cancer tissues as detected by immunohistochemistry. To further study how RhoGDI2 up-regulates P-gp expression, we tested the activity of Rac1 in MKN-45/RhoGDI2 and MKN-45/GFP. Ectopic expression of RhoGDI2 increased Rac1 activity (P < 0.05). For more important, silencing of Rac1 expression by siRNA decreased P-gp expression to undetectable level. Overall, these findings suggest that RhoGDI2 up-regulates P-gp expression via Rac1 to induce MDR.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-015-0190-4) contains supplementary material, which is available to authorized users.

Phospholipids and cholesterol: Inducers of cancer multidrug resistance and therapeutic targets

“…Interestingly, the Rho-GDP dissociation inhibitor 2 (RhoGDI2), that reduces Rho activity by preventing its dissociation from GDP, up-regulates Pgp in gastric cancer cells and increases the resistance to 5-fluorouracle. In this case, however, the effects on Pgp are not mediated by the activation of Rho, but by the activation of Rac1, as demonstrated by the down-regulation of Pgp in Rac1-silenced cells (Zheng et al, 2015). By contrast, the inhibition of RhoA reduces the expression of Pgp and MRP1 in irinotecan-resistant colorectal cancer cells (Ruihua et al, 2016), in line with previous observations (Riganti et al, 2013).…”

Intercellular transfer of P-glycoprotein in human blood-brain barrier endothelial cells is increased by histone deacetylase inhibitors

“…We next addressed the question whether the transferred Pgp-EGFP fusion protein is functional. For this purpose, we performed flow cytometry experiments with the fluorescent Pgp substrate eFLUXX-ID Gold, which allows multiplexing with EGFP-expressing cell lines and has been used as an indicator of a multidrug resistant phenotype 21 23 24 31 32 . Furthermore, the Pgp inhibitors tariquidar and verapamil were utilized to quantitatively measure functionality of Pgp in the co-cultures of hCMEC/D3-MDR1-EGFP (−/+) and eFluor670 labeled hCMEC/D3 cells (+/−) as well as eFluor670 labeled hCMEC/D3 cells which received the Pgp-EGFP fusion protein (+/+) ( Figs 3 a,b and S2).…”

Silencing of long non-coding RNA ANRIL inhibits the development of multidrug resistance in gastric cancer cells

“…Classical drug-resistant molecules, such as multidrug resistance gene 1 (MDR1) (2) and multi-drug resistance protein (MRP1) (3), have been found to play important roles in mediating MDR in some gastric cancers. However, the efficacy of chemotherapy for gastric cancer is limited due to insensitivity and the development of MDR (4).…”