title: ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways.
abstract: In the normal human colon, aldehyde dehydrogenase 1B1 (ALDH1B1) is expressed only at the crypt base, along with stem cells. It is also highly expressed in the human colonic adenocarcinomas. This pattern of expression corresponds closely to that observed for Wnt/β-catenin signaling activity. The present study examines the role of ALDH1B1 in colon tumorigenesis and signalling pathways mediating its effects. In a 3-dimensional spheroid growth model and a nude mouse xenograft tumor model, shRNA-induced suppression of ALDH1B1 expression decreased the number and size of spheroids formed in vitro and the size of xenograft tumors formed in vivo by SW 480 cells. Six binding elements for Wnt/β-catenin signalling transcription factor binding elements (T-cell factor/lymphoid enhancing factor) were identified in the human ALDH1B1 gene promoter (3 kb) but shown by dual luciferase reporter assay to not be necessary for ALDH1B1 mRNA expression in colon adenocarcinoma cell lines. We examined Wnt-reporter activity and protein/mRNA expression for Wnt, Notch and PI3K/Akt signaling pathways. Wnt/β-catenin, Notch and PI3K/Akt-signaling pathways were down-regulated in SW 480 cells in which ALDH1B1 expression had been suppressed. In summary, our data demonstrate that ALDH1B1 may promote colon cancer tumorigenesis by modulating the Wnt/β-catenin, Notch and PI3K/Akt signaling pathways. Selective targeting of ALDH1B1 may represent a novel means to prevent or treat colon cancer.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Surendra
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Arcaroli
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Thompson
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Wells
authors.initials: W
authors.lastname: Messersmith
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Vasiliou
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000502:physiology; D060449:Wnt Signaling Pathway
chemical_list: D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D051880:Receptors, Notch; C524846:ALDH1B1 protein, human