Identification of genes conferring resistance to 5-fluorouracil.
Astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human hepatocellular carcinoma (HCC) patients and plays a significant role in mediating aggressive progression of HCC. AEG-1 is known to augment invasion, metastasis, and angiogenesis, and we now demonstrate that AEG-1 directly contributes to another important hallmark of aggressive cancers, that is, resistance to chemotherapeutic drugs, such as 5-fluorouracil (5-FU). AEG-1 augments expression of the transcription factor LSF that regulates the expression of thymidylate synthase (TS), a target of 5-FU. In addition, AEG-1 enhances the expression of dihydropyrimidine dehydrogenase (DPYD) that catalyzes the initial and rate-limiting step in the catabolism of 5-FU. siRNA-mediated inhibition of AEG-1, LSF, or DPYD significantly increased the sensitivity of HCC cells to 5-FU in vitro and a lentivirus delivering AEG-1 siRNA in combination with 5-FU markedly inhibited growth of HCC cells xenotransplanted in athymic nude mice when compared to either agent alone. The present studies highlight 2 previously unidentified genes, AEG-1 and LSF, contributing to chemoresistance. Inhibition of AEG-1 might be exploited as a therapeutic strategy along with 5-FU-based combinatorial chemotherapy for HCC, a highly fatal cancer with currently very limited therapeutic options.
Yoo
Byoung Kwon
BK
Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Gredler
Rachel
R
Vozhilla
Nicollaq
N
Su
Zao-zhong
ZZ
Chen
Dong
D
Forcier
Talitha
T
Shah
Khalid
K
Saxena
Utsav
U
Hansen
Ulla
U
Fisher
Paul B
PB
Sarkar
Devanand
D
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D016601:RNA-Binding Proteins; D013940:Thymidylate Synthase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D000964:Antimetabolites, Antineoplastic; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C501906:TFCP2 protein, human; D014157:Transcription Factors; D004247:DNA; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil