title: Aldehyde Dehydrogenase Is Regulated by β-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells.
abstract: Radiotherapy is a curative treatment option in prostate cancer. Nevertheless, patients with high-risk prostate cancer are prone to relapse. Identification of the predictive biomarkers and molecular mechanisms of radioresistance bears promise to improve cancer therapies. In this study, we show that aldehyde dehydrogenase (ALDH) activity is indicative of radioresistant prostate progenitor cells with an enhanced DNA repair capacity and activation of epithelial-mesenchymal transition (EMT). Gene expression profiling of prostate cancer cells, their radioresistant derivatives, ALDH(+) and ALDH(-) cell populations revealed the mechanisms, which link tumor progenitors to radioresistance, including activation of the WNT/β-catenin signaling pathway. We found that expression of the ALDH1A1 gene is regulated by the WNT signaling pathway and co-occurs with expression of β-catenin in prostate tumor specimens. Inhibition of the WNT pathway led to a decrease in ALDH(+) tumor progenitor population and to radiosensitization of cancer cells. Taken together, our results indicate that ALDH(+) cells contribute to tumor radioresistance and their molecular targeting may enhance the effectiveness of radiotherapy.
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany.
authors: Monica
authors: M
authors: Cojoc
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany. Anna.Dubrovska@OncoRay.de Claudia.Peitzsch@OncoRay.de.
authors: Claudia
authors: C
authors: Peitzsch
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany.
authors: Ina
authors: I
authors: Kurth
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany.
authors: Franziska
authors: F
authors: Trautmann
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany.
authors: Leoni A
authors: LA
authors: Kunz-Schughart
authors: Institute of Molecular Biology and Genetics NAS of Ukraine, Kyiv, Ukraine.
authors: Gennady D
authors: GD
authors: Telegeev
authors: National Cancer Institute, Kyiv, Ukraine.
authors: Eduard A
authors: EA
authors: Stakhovsky
authors: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors: John R
authors: JR
authors: Walker
authors: UMass Cancer Center Tissue Bank, Department of Cancer Biology, UMass Medical School, Worcester, Massachusetts.
authors: Karl
authors: K
authors: Simin
authors: UMass Cancer Center Tissue Bank, Department of Cancer Biology, UMass Medical School, Worcester, Massachusetts.
authors: Stephen
authors: S
authors: Lyle
authors: Department of Urology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany.
authors: Susanne
authors: S
authors: Fuessel
authors: Department of Urology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany.
authors: Kati
authors: K
authors: Erdmann
authors: Department of Urology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany.
authors: Manfred P
authors: MP
authors: Wirth
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany. Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany. Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Germany, Bautzner Landstrasse, Dresden, Germany. German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Mechthild
authors: M
authors: Krause
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany. Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany. Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Germany, Bautzner Landstrasse, Dresden, Germany. German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Michael
authors: M
authors: Baumann
authors: OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany. German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. Anna.Dubrovska@OncoRay.de Claudia.Peitzsch@OncoRay.de.
authors: Anna
authors: A
authors: Dubrovska
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D011836:Radiation Tolerance; D050697:Retinal Dehydrogenase; D059467:Transcriptome; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase