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Role in tumor growth of a glycogen debranching enzyme lost in glycogen storage disease.
Guin, Sunny; Pollard, Courtney; Ru, Yuanbin; Ritterson Lew, Carolyn; Duex, Jason E; Dancik, Garrett; Owens, Charles; Spencer, Andrea; Knight, Scott; Holemon, Heather; Gupta, Sounak; Hansel, Donna; Hellerstein, Marc; Lorkiewicz, Pawel; Lane, Andrew N; Fan, Teresa W-M; Theodorescu, Dan.
Afiliación
  • Guin S; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Pollard C; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Ru Y; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Ritterson Lew C; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Duex JE; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Dancik G; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Owens C; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Spencer A; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Knight S; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Holemon H; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Gupta S; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Hansel D; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Hellerstein M; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Lorkiewicz P; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Lane AN; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Fan TW; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
  • Theodorescu D; Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Clevel
J Natl Cancer Inst ; 106(5)2014 Apr 03.
Article en En | MEDLINE | ID: mdl-24700805
ABSTRACT

BACKGROUND:

Bladder cancer is the most common malignancy of the urinary system, yet our molecular understanding of this disease is incomplete, hampering therapeutic advances.

METHODS:

Here we used a genome-wide functional short-hairpin RNA (shRNA) screen to identify suppressors of in vivo bladder tumor xenograft growth (n = 50) using bladder cancer UMUC3 cells. Next-generation sequencing was used to identify the most frequently occurring shRNAs in tumors. Genes so identified were studied in 561 patients with bladder cancer for their association with stratification of clinical outcome by Kaplan-Meier analysis. The best prognostic marker was studied to determine its mechanism in tumor suppression using anchorage-dependent and -independent growth, xenograft (n = 20), and metabolomic assays. Statistical significance was determined using two-sided Student t test and repeated-measures statistical analysis.

RESULTS:

We identified the glycogen debranching enzyme AGL as a prognostic indicator of patient survival (P = .04) and as a novel regulator of bladder cancer anchorage-dependent (P < .001), anchorage-independent (mean ± standard deviation, 180 ± 23.1 colonies vs 20±9.5 in control, P < .001), and xenograft growth (P < .001). Rescue experiments using catalytically dead AGL variants revealed that this effect is independent of AGL enzymatic functions. We demonstrated that reduced AGL enhances tumor growth by increasing glycine synthesis through increased expression of serine hydroxymethyltransferase 2.

CONCLUSIONS:

Using an in vivo RNA interference screen, we discovered that AGL, a glycogen debranching enzyme, has a biologically and statistically significant role in suppressing human cancer growth.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias de la Vejiga Urinaria / Sistema de la Enzima Desramificadora del Glucógeno Límite: Animals / Humans / Male Idioma: En Revista: J Natl Cancer Inst Año: 2014 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias de la Vejiga Urinaria / Sistema de la Enzima Desramificadora del Glucógeno Límite: Animals / Humans / Male Idioma: En Revista: J Natl Cancer Inst Año: 2014 Tipo del documento: Article