Reversal of P-glycoprotein-mediated multi-drug resistance by the E3 ubiquitin ligase Cbl-b in human gastric adenocarcinoma cells.
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.
Zhang
Ye
Y
Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, People's Republic of China.
Qu
Xiujuan
X
Hu
Xuejun
X
Yang
Xianghong
X
Hou
Kezuo
K
Teng
Yuee
Y
Zhang
Jingdong
J
Sada
Kiyonao
K
Liu
Yunpeng
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004317:Doxorubicin / Q000032:analysis / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050721:Proto-Oncogene Proteins c-cbl / Q000032:analysis / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004317:Doxorubicin; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D051058:Oncogene Protein v-akt