Reversal of P‐glycoprotein‐mediated multi‐drug resistance by the E3 ubiquitin ligase Cbl‐b in human gastric adenocarcinoma cells

Abstract

P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) is a major barrier to the effective chemotherapy of many cancers. Recent studies have shown that inhibition of the PI3K/Akt signalling pathway can reverse P-gp-mediated MDR. We investigated the expression of activated Akt (p-Akt) in 124 human gastric carcinoma tissue samples. Ubiquitous p-Akt expression was recorded in the majority (88/124). There was a significant correlation between p-Akt expression and the expression of P-gp. In the adriamycin-resistant MDR gastric carcinoma cell line SGC7901/ADR, p-Akt expression was increased in comparison with the parental cell line SGC7901. Treatment of SGC7901/ADR cells with the PI3K inhibitor LY294002 reduced the expression of both p-Akt and P-gp. To explore the role of ubiquitin ligase Cbl-b in this regulatory pathway, SGC7901/ADR cells were transfected with a plasmid overexpressing wild-type Cbl-b. This down-regulated the expression of both p-Akt and P-gp. Furthermore, resistance to chemotherapeutic drugs was partially reversed. These results demonstrate an important role for Cbl-b in reversing P-gp-mediated gastric cancer MDR through suppression of the PI3K/Akt signalling pathway and the down-regulation of P-gp expression.

Sensitivity of Gastric Cancer Cells to Chemotherapy Drugs in Elderly Patients and Its Correlation with Cyclooxygenase-2 Expression

“…All of GST-π, P-gp and TopoIIα belong to typical MDR-related factors, and their-induced MDR phenotypes are the markers of acquired or intrinsic drug-resistance. By different pathways including binding to enzymes and drug-pump effect, both GST-π and P-gp can make a variety of chemotherapy drugs discharge from the body to induce MDR (Zhang et al, 2009). As a crucial target in the chemotherapy, up-regulation of TopoIIα expression can reinforce the sensitivity of tumor cells to chemotherapy drugs (Shi et al, 2008).…”

New Insights into the Mechanisms of Gastric Cancer Multidrug Resistance and Future Perspectives

“…Treatment of SGC7901/ADR cells with the PI3K inhibitor LY294002 reduced the expression of both p-Akt and P-gp. Forced over expression of Cbl-b in SGC7901/ADR cells reduced the expression of both phospho-Akt and P-gp and partially reversed the resistance phenotype to chemotherapeutic agents [68]. miRNAs miRNAs are endogenous, small, noncoding RNAs that regulate gene expression at the posttranscriptional level.…”

Expression of ADP-ribosyltransferase 1 Is Associated with Poor Prognosis of Glioma Patients

“…Several studies reported that TUBB3 was involved in the resistance of VCR in gastric cancer and lung cancer (Nardone et al 2004;Gan et al 2007;Zhang et al 2009Zhang et al , 2013Fetisova et al 2010;Li et al 2015). We thus analyzed the expression of TUBB3 in our experiments.…”