title: Molecular mechanism of chemoresistance by astrocyte elevated gene-1.
abstract: Our recent findings show that astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human hepatocellular carcinoma (HCC) samples, and AEG-1 plays a central role in regulating development and progression of HCC. In the present study, we elucidate a molecular mechanism of AEG-1-induced chemoresistance, an important characteristic of aggressive cancers. AEG-1 increases the expression of multidrug resistance gene 1 (MDR1) protein, resulting in increased efflux and decreased accumulation of doxorubicin, promoting doxorubicin resistance. Suppression of MDR1 by small interfering RNA or chemical reagents, or inhibition of AEG-1 or a combination of both genes, significantly increases in vitro sensitivity to doxorubicin. In nude mice xenograft studies, a lentivirus expressing AEG-1 short hairpin RNA, in combination with doxorubicin, profoundly inhibited growth of aggressive human HCC cells compared with either agent alone. We document that although AEG-1 does not affect MDR1 gene transcription, it facilitates association of MDR1 mRNA to polysomes, resulting in increased translation, and AEG-1 also inhibits ubiquitination and subsequent proteasome-mediated degradation of MDR1 protein. This study is the first documentation of a unique aspect of AEG-1 function (i.e., translational and posttranslational regulation of proteins). Inhibition of AEG-1 might provide a means of more effectively using chemotherapy to treat HCC, which displays inherent chemoresistance with aggressive pathology.
authors.affiliation: Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, and VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298, USA.
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Yoo
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Zhao-Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.forename: Jinsang
authors.initials: J
authors.lastname: Yoo
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000502:physiology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008113:Liver Neoplasms / Q000201:enzymology*; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D004317:Doxorubicin
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