title: The Leloir Pathway of Galactose Metabolism - A Novel Therapeutic Target for Hepatocellular Carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most lethal types of cancer worldwide, with poor prognosis and limited treatments. In order to identify novel therapeutic targets that will lead to development of effective therapies with manageable side effects, we tested the hypothesis that knocking-down galactokinase (GALK1) or galactose-1 phosphate uridylyltransferase (GALT) gene expression would control the growth of cultured hepatoma cells. Our results showed small interfering RNA (siRNA) against GALK1 or GALT inhibited the growth of HepG2 cells in culture. Western blot analysis revealed simultaneous down-regulation of multiple players of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) growth signaling pathway, as well as heat-shock protein 90 (HSP90) and poly ADP ribose polymerase (PARP). Reverse transcription-polymerase chain reaction (RT-PCR) data, however, showed no significant mRNA reduction of the encoded genes. Our study thus not only supports GALK1 and GALT as being possible novel targets for treating HCC, but also uncovers new post-transcriptional regulatory mechanisms that link the galactose metabolic pathway to protein expression of the PI3K/AKT pathway in hepatoma.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. manshu.tang@hsc.utah.edu kent.lai@hsc.utah.edu.
authors.forename: Manshu
authors.initials: M
authors.lastname: Tang
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, U.S.A.
authors.forename: Enoabasi
authors.initials: E
authors.lastname: Etokidem
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. manshu.tang@hsc.utah.edu kent.lai@hsc.utah.edu.
authors.forename: Kent
authors.initials: K
authors.lastname: Lai
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000628:therapy; D005686:Galactokinase / Q000235:genetics / Q000378:metabolism; D005690:Galactose / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000628:therapy*; D034741:RNA, Small Interfering; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C484715:GALK1 protein, human; D005686:Galactokinase; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase; D005690:Galactose
keywords: Galactose metabolism; HSP90; HepG2; PARP; PI3K/AKT; galactokinase; galactose -1 phosphate uridylyltransferase; hepatocellular carcinoma; siRNA