title: ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis.
abstract: We hypothesize that aldehyde dehydrogenase 1A1 (ALDH1A1) deficiency will result in impaired ataxia-telangiectasia mutated (ATM) activation in a retinoic acid-sensitive fashion. Data supporting this hypothesis include (1) reduced ATM activation in irradiated primary dermal fibroblasts from ALDH1A1-deficient Gorlin syndrome patients (GDFs), relative to ALDH1A1-positive normal human dermal fibroblasts (NHDFs) and (2) increased ATM activation by X-radiation in GDFs pretreated with retinoic acid, however, the impact of donor variability on ATM activation in fibroblasts was not assessed and is a prudent consideration in future studies. Clonogenic survival of irradiated cells showed differential responses to retinoic acid as a function of treatment time. Long-term (5 Day) retinoic acid treatment functioned as a radiosensitizer and was associated with downregulation of ATM protein levels. Short-term (7 h) retinoic acid treatment showed a trend toward increased survival of irradiated cells and did not downregulate ATM protein levels. Using a newly developed IncubATR technology, which defines changes in bulk chemical bond patterns in live cells, we can discriminate between the NHDF and GDF phenotypes, but treatment of GDFs with retinoic acid does not induce reversion of bulk chemical bond patterns associated with GDFs toward the NHDF phenotype. Collectively, our preliminary investigation of the Gorlin phenotype has identified deficient ALDH1A1 expression associated with deficient ATM activation as a possible susceptibility factor that is consistent with the high incidence of spontaneous and radiation-induced carcinogenesis in these patients. The IncubATR technology exhibits sufficient sensitivity to detect phenotypic differences in live cells that may be relevant to radiation health effects.
authors.affiliation: Systems Toxicology and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99352, USA. Thomas.Weber@pnnl.gov.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Weber
authors.affiliation: Faculté de Médicine, 2ème étage, CNRS UMR 6267-INSERM U998-UNSA, Nice 06107 Cedex 2, France. Thierry.Magnaldo@unice.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Magnaldo
authors.affiliation: College of Osteopathic Medicine of the Pacific-Northwest, Western University of Health Sciences, Lebanon, OR 97355, USA. yxiong@westernu.edu.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Xiong
keywords: ATM; Gorlin; carcinogenesis; retinoic acid