|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
39
|
|
pubmed:dateCreated |
2009-9-21
|
|
pubmed:abstractText |
Epirubicin has been widely used for chemotherapeutic treatment of gastric cancer; however, intrinsic and acquired chemoresistance remains an obstacle to successful management. The mechanisms underlying epirubicin resistance are still not well defined. Here we report the construction and application of a partially randomized retrovirus library of 4 x 10(6) small interfering RNAs to identify novel genes whose suppression confers epirubicin resistance in gastric cancer cells SGC7901. From 12 resistant cell colonies, two small interfering RNAs targeting GAS1 (growth arrest-specific 1) and PTEN (phosphatase and tensin homolog), respectively, were identified and validated. We identified a previously unrecognized chemoresistance role for GAS1. GAS1 suppression resulted in significant epirubicin resistance and cross-resistance to 5-fluorouracil and cisplatin in various gastric cancer cell lines. GAS1 suppression promoted multidrug resistance through apoptosis inhibition, partially by up-regulating the Bcl-2/Bax ratio that was abolished by Bcl-2 inhibition. GAS1 suppression induced chemoresistance partially by increasing drug efflux in an ATP-binding cassette transporter and drug-dependent manner. P-glycoprotein (P-gp) and BCRP (breast cancer resistance protein) but not MRP-1 were up-regulated, and targeted knockdown of P-gp and BCRP could partially reverse GAS1 suppression-induced epirubicin resistance. Verapamil, a P-gp inhibitor, could reverse P-gp substrate (epirubicin) but not non-P-gp substrate (5-fluorouracil and cisplatin) resistance in GAS1-suppressed gastric cancer cells. BCRP down-regulation could partially reverse 5-fluorouracil but not cisplatin resistance induced by GAS1 suppression, suggesting 5-fluorouracil but not cisplatin was a BCRP substrate. These results suggest that GAS1 might be a target to overcome multidrug resistance and provide a novel approach to identifying candidate genes that suppress chemoresistance of gastric cancers.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/ABCG2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/ATP-Binding Cassette Transporters,
http://linkedlifedata.com/resource/pubmed/chemical/Antibiotics, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/BAX protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cisplatin,
http://linkedlifedata.com/resource/pubmed/chemical/Epirubicin,
http://linkedlifedata.com/resource/pubmed/chemical/Fluorouracil,
http://linkedlifedata.com/resource/pubmed/chemical/GAS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/GPI-Linked Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/P-Glycoprotein,
http://linkedlifedata.com/resource/pubmed/chemical/PTEN Phosphohydrolase,
http://linkedlifedata.com/resource/pubmed/chemical/PTEN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-2-Associated X Protein
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Sep
|
|
pubmed:issn |
1083-351X
|
|
pubmed:author |
pubmed-author:FanDaimingD,
pubmed-author:GangYiY,
pubmed-author:HeLijieL,
pubmed-author:HonghongWangW,
pubmed-author:JinHaifengH,
pubmed-author:KimW EWE,
pubmed-author:LiTingtingT,
pubmed-author:LinXiaX,
pubmed-author:LiuZhiguoZ,
pubmed-author:PanYanglinY,
pubmed-author:QiaoTaidongT,
pubmed-author:YaoLipingL,
pubmed-author:ZhangYongguoY,
pubmed-author:ZhaoLinaL
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
25
|
|
pubmed:volume |
284
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
26273-85
|
|
pubmed:dateRevised |
2010-11-18
|
|
pubmed:meshHeading |
pubmed-meshheading:19638344-ATP-Binding Cassette Transporters,
pubmed-meshheading:19638344-Antibiotics, Antineoplastic,
pubmed-meshheading:19638344-Apoptosis,
pubmed-meshheading:19638344-Base Sequence,
pubmed-meshheading:19638344-Blotting, Western,
pubmed-meshheading:19638344-Cell Cycle Proteins,
pubmed-meshheading:19638344-Cell Line, Tumor,
pubmed-meshheading:19638344-Cell Survival,
pubmed-meshheading:19638344-Cisplatin,
pubmed-meshheading:19638344-Drug Resistance, Multiple,
pubmed-meshheading:19638344-Drug Resistance, Neoplasm,
pubmed-meshheading:19638344-Epirubicin,
pubmed-meshheading:19638344-Flow Cytometry,
pubmed-meshheading:19638344-Fluorouracil,
pubmed-meshheading:19638344-GPI-Linked Proteins,
pubmed-meshheading:19638344-Gene Library,
pubmed-meshheading:19638344-Humans,
pubmed-meshheading:19638344-Membrane Proteins,
pubmed-meshheading:19638344-Molecular Sequence Data,
pubmed-meshheading:19638344-Neoplasm Proteins,
pubmed-meshheading:19638344-P-Glycoprotein,
pubmed-meshheading:19638344-PTEN Phosphohydrolase,
pubmed-meshheading:19638344-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:19638344-RNA, Small Interfering,
pubmed-meshheading:19638344-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:19638344-Stomach Neoplasms,
pubmed-meshheading:19638344-Transfection,
pubmed-meshheading:19638344-bcl-2-Associated X Protein
|
|
pubmed:year |
2009
|
|
pubmed:articleTitle |
Identification of GAS1 as an epirubicin resistance-related gene in human gastric cancer cells with a partially randomized small interfering RNA library.
|
|
pubmed:affiliation |
State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China.
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|
