Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis
Abstract
Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of relevant pathways/networks. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol-reactive probes with a flexible click chemistry functional group to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. We observe qualitative differences in protein thiol profiles by SDS-PAGE analysis when detection by iodoacetamide vs maleimide probe chemistries are compared, and pretreatment of cells with hydrogen peroxide eliminates detection of the majority of SDS-PAGE bands. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent donors, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and this deficiency was confirmed by Western blot. Redox probes revealed additional protein thiol differences between GDFs and NHDFs, including radiation responsive annexin family members. Our results indicate a multifactorial basis for the unusual sensitivitymore »
- Authors:
-
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Omic Biological Applications
- Centre national de la recherche scientifique (CNRS), Nice (France). Faculte de Medicine
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Systems Toxicology Group
- Centre national de la recherche scientifique (CNRS), Nice (France). Inst. for Research on Cancer and Aging
- Systems Toxicology Group, Pacific Northwest National Laboratory, Richland Washington
- Publication Date:
- Research Org.:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1203899
- Report Number(s):
- PNNL-SA-95210
Journal ID: ISSN 0899-1987; 47292; KP1602020
- Grant/Contract Number:
- AC05-76RL01830; 8P41GM103493-10; ET9-551; SFI201212055859
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Molecular Carcinogenesis
- Additional Journal Information:
- Journal Volume: 54; Journal Issue: 6; Journal ID: ISSN 0899-1987
- Publisher:
- Wiley
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 62 RADIOLOGY AND NUCLEAR MEDICINE; Gorlin syndrome; radiation; retinoic acid; carcinogenesis; protein thiol; Environmental Molecular Sciences Laboratory
Citation Formats
Wright, Aaron T., Magnaldo, Thierry, Sontag, Ryan L., Anderson, Lindsey N., Sadler, Natalie C., Piehowski, Paul D., Gache, Yannick, and Weber, Thomas J. Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis. United States: N. p., 2013.
Web. doi:10.1002/mc.22115.
Wright, Aaron T., Magnaldo, Thierry, Sontag, Ryan L., Anderson, Lindsey N., Sadler, Natalie C., Piehowski, Paul D., Gache, Yannick, & Weber, Thomas J. Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis. United States. https://doi.org/10.1002/mc.22115
Wright, Aaron T., Magnaldo, Thierry, Sontag, Ryan L., Anderson, Lindsey N., Sadler, Natalie C., Piehowski, Paul D., Gache, Yannick, and Weber, Thomas J. Wed .
"Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis". United States. https://doi.org/10.1002/mc.22115. https://www.osti.gov/servlets/purl/1203899.
@article{osti_1203899,
title = {Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis},
author = {Wright, Aaron T. and Magnaldo, Thierry and Sontag, Ryan L. and Anderson, Lindsey N. and Sadler, Natalie C. and Piehowski, Paul D. and Gache, Yannick and Weber, Thomas J.},
abstractNote = {Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of relevant pathways/networks. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol-reactive probes with a flexible click chemistry functional group to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. We observe qualitative differences in protein thiol profiles by SDS-PAGE analysis when detection by iodoacetamide vs maleimide probe chemistries are compared, and pretreatment of cells with hydrogen peroxide eliminates detection of the majority of SDS-PAGE bands. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent donors, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and this deficiency was confirmed by Western blot. Redox probes revealed additional protein thiol differences between GDFs and NHDFs, including radiation responsive annexin family members. Our results indicate a multifactorial basis for the unusual sensitivity of Gorlin syndrome to radiation carcinogenesis, and the pathways identified have plausible implications for radiation health effects.},
doi = {10.1002/mc.22115},
journal = {Molecular Carcinogenesis},
number = 6,
volume = 54,
place = {United States},
year = {Wed Nov 27 00:00:00 EST 2013},
month = {Wed Nov 27 00:00:00 EST 2013}
}
Web of Science
Works referenced in this record:
Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome
journal, March 1997
- Kimonis, V. E.; Goldstein, A. M.; Pastakia, B.
- American Journal of Medical Genetics, Vol. 69, Issue 3
Síndrome del nevo basocelular: experiencia en un hospital pediátrico
journal, June 2013
- Samela, P. C.; Tosi, V.; Cervini, A. B.
- Actas Dermo-Sifiliográficas, Vol. 104, Issue 5
Hedgehog Signaling in Development and Cancer
journal, December 2008
- Jiang, Jin; Hui, Chi-chung
- Developmental Cell, Vol. 15, Issue 6
Radiation-induced brain tumours in nevoid basal cell carcinoma syndrome: implications for treatment and surveillance
journal, September 2006
- Choudry, Q.; Patel, H. C.; Gurusinghe, N. T.
- Child's Nervous System, Vol. 23, Issue 1
Brain tumours and the occurrence of severe invasive basal cell carcinoma in first degree relatives with Gorlin syndrome
journal, January 1991
- Evans, D. Gareth R.; Birch, Jillian M.; Orton, Clive I.
- British Journal of Neurosurgery, Vol. 5, Issue 6
Nevoid basal cell carcinoma syndrome: Relation with desmoplastic medulloblastoma in infancy
journal, July 2003
- Amlashi, Seyed F. A.; Riffaud, Laurent; Brassier, Gilles
- Cancer, Vol. 98, Issue 3
Multiple tumor types including leiomyoma and Wilms tumor in a patient with Gorlin syndrome due to 9q22.3 microdeletion encompassing the PTCH1 and FANC-C loci
journal, October 2013
- Garavelli, Livia; Piemontese, Maria Rosaria; Cavazza, Alberto
- American Journal of Medical Genetics Part A, Vol. 161, Issue 11
Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes
journal, September 2005
- Evans, D. G. R.
- Journal of Medical Genetics, Vol. 43, Issue 4
Somatic mutations in thePTCH,SMOH,SUFUHandTP53genes in sporadic basal cell carcinomas
journal, January 2005
- Reifenberger, J.; Wolter, M.; Knobbe, C. B.
- British Journal of Dermatology, Vol. 152, Issue 1
Radiobiological studies in the naevoid basal cell carcinoma syndrome
journal, November 1990
- Ewton, Julia A.; Black, Anne Kobza; Arlett, C. F.
- British Journal of Dermatology, Vol. 123, Issue 5
Multiple abnormalities in the ultraviolet light response of cultured fibroblasts derived from patients with the basal cell nevus syndrome
journal, January 1988
- Nagasawa, H.; Burke, M. J.; Little, F. F.
- Teratogenesis, Carcinogenesis, and Mutagenesis, Vol. 8, Issue 1
Ultraviolet responses of Gorlin syndrome primary skin cells
journal, August 2008
- Brellier, F.; Valin, A.; Chevallier-Lagente, O.
- British Journal of Dermatology, Vol. 159, Issue 2
Xeroderma pigmentosum
journal, January 2011
- Lehmann, Alan R.; McGibbon, David; Stefanini, Miria
- Orphanet Journal of Rare Diseases, Vol. 6, Issue 1
Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions
journal, May 2013
- Ambrose, Mark; Gatti, Richard A.
- Blood, Vol. 121, Issue 20
A new paradigm in toxicology and teratology: Altering gene activity in the absence of DNA sequence variation
journal, July 2007
- Reamon-Buettner, Stella Marie; Borlak, Jürgen
- Reproductive Toxicology, Vol. 24, Issue 1
Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum
journal, August 2008
- Mancuso, M.; Pasquali, E.; Leonardi, S.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 34
Sonic Hedgehog signaling impairs ionizing radiation–induced checkpoint activation and induces genomic instability
journal, October 2008
- Leonard, Jennifer M.; Ye, Hong; Wetmore, Cynthia
- Journal of Cell Biology, Vol. 183, Issue 3
PTCH1+/− Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts
journal, March 2009
- Valin, Alexandre; Barnay-Verdier, Stéphanie; Robert, Thomas
- PLoS ONE, Vol. 4, Issue 3
Tumor stroma as targets for cancer therapy
journal, February 2013
- Zhang, Jing; Liu, Jinsong
- Pharmacology & Therapeutics, Vol. 137, Issue 2
Low-Dose Radiation-Induced Senescent Stromal Fibroblasts Render Nearby Breast Cancer Cells Radioresistant
journal, September 2009
- Tsai, Kelvin K. C.; Stuart, Jeremy; Chuang, Yao-Yu Eric
- Radiation Research, Vol. 172, Issue 3
Oxidative stress caused by a low concentration of hydrogen peroxide induces senescence-like changes in mouse gingival fibroblasts
journal, August 2012
- Kiyoshima, Tamotsu; Enoki, Norio; Kobayashi, Ieyoshi
- International Journal of Molecular Medicine, Vol. 30, Issue 5
Effects of redox modulation by inhibition of thioredoxin reductase on radiosensitivity and gene expression
journal, June 2012
- Selenius, Markus; Hedman, Mattias; Brodin, David
- Journal of Cellular and Molecular Medicine, Vol. 16, Issue 7
Radiation Response of Cells during Altered Protein Thiol Redox
journal, April 2003
- Biaglow, John E.; Ayene, Iraimoudi S.; Koch, Cameron J.
- Radiation Research, Vol. 159, Issue 4
Involvement of ERK-Nrf-2 Signaling in Ionizing Radiation Induced Cell Death in Normal and Tumor Cells
journal, June 2013
- Patwardhan, Raghavendra S.; Checker, Rahul; Sharma, Deepak
- PLoS ONE, Vol. 8, Issue 6
NRF2 Cysteine Residues Are Critical for Oxidant/Electrophile-Sensing, Kelch-Like ECH-Associated Protein-1-Dependent Ubiquitination-Proteasomal Degradation, and Transcription Activation
journal, September 2009
- He, Xiaoqing; Ma, Qiang
- Molecular Pharmacology, Vol. 76, Issue 6
The Disulfide Proteome and Other Reactive Cysteine Proteomes: Analysis and Functional Significance
journal, June 2011
- Lindahl, Marika; Mata-Cabana, Alejandro; Kieselbach, Thomas
- Antioxidants & Redox Signaling, Vol. 14, Issue 12
Detection of reversible protein thiol modifications in tissues
journal, November 2006
- Rogers, Lynette K.; Leinweber, Barbara L.; Smith, Charles V.
- Analytical Biochemistry, Vol. 358, Issue 2
Identification of Widespread Adenosine Nucleotide Binding in Mycobacterium tuberculosis
journal, January 2013
- Ansong, Charles; Ortega, Corrie; Payne, Samuel H.
- Chemistry & Biology, Vol. 20, Issue 1
A paracrine signal mediates the cell transformation response to low dose gamma radiation in JB6 cells
journal, January 2005
- Weber, Thomas J.; Siegel, Robert W.; Markillie, Lye M.
- Molecular Carcinogenesis, Vol. 43, Issue 1
Suite of Activity-Based Probes for Cellulose-Degrading Enzymes
journal, December 2012
- Chauvigné-Hines, Lacie M.; Anderson, Lindsey N.; Weaver, Holly M.
- Journal of the American Chemical Society, Vol. 134, Issue 50
Method to Correlate Tandem Mass Spectra of Modified Peptides to Amino Acid Sequences in the Protein Database
journal, April 1995
- Yates, John R.; Eng, Jimmy K.; McCormack, Ashley L.
- Analytical Chemistry, Vol. 67, Issue 8
Spectral Probabilities and Generating Functions of Tandem Mass Spectra: A Strike against Decoy Databases
journal, August 2008
- Kim, Sangtae; Gupta, Nitin; Pevzner, Pavel A.
- Journal of Proteome Research, Vol. 7, Issue 8
Annexin A2 Modulates Radiation-Sensitive Transcriptional Programming and Cell Fate
journal, January 2013
- Waters, Katrina M.; Stenoien, David L.; Sowa, Marianne B.
- Radiation Research, Vol. 179, Issue 1
DDM-PGE2-mediated cytoprotection in renal epithelial cells by a thromboxane A2receptor coupled to NF-κB
journal, February 2000
- Weber, Thomas J.; Monks, Terrence J.; Lau, Serrine S.
- American Journal of Physiology-Renal Physiology, Vol. 278, Issue 2
Lack of evidence for low-LET radiation induced bystander response in normal human fibroblasts and colon carcinoma cells
journal, February 2010
- Sowa, Marianne B.; Goetz, Wilfried; Baulch, Janet E.
- International Journal of Radiation Biology, Vol. 86, Issue 2
Reactive Oxygen Species and DNA Damage in 2-Bromo-(glutathione-S-yl) hydroquinone-Mediated Cytotoxicity
journal, June 1995
- Mertens, J. J. W. M.; Gibson, N. W.; Lau, S. S.
- Archives of Biochemistry and Biophysics, Vol. 320, Issue 1
Radiation-induced versus endogenous DNA damage and assays that measure parameters reflecting DNA damage on cell by cell basis: comments on the article by Pollycove and Feinendegen
journal, June 2003
- Roti Roti, Joseph L.
- Human & Experimental Toxicology, Vol. 22, Issue 6
Annexin A2 is a novel Cellular Redox Regulatory Protein involved in Tumorigenesis
journal, December 2011
- Madureira, Patricia Alexandra; Hill, Richard; Miller, Victoria Ann
- Oncotarget, Vol. 2, Issue 12
S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen receptors
journal, January 2005
- Kwon, Mijung,
- Frontiers in Bioscience, Vol. 10, Issue 1-3
Regulation of the Low-Dose Radiation Paracrine-Specific Anchorage-Independent Growth Response by Annexin A2
journal, July 2009
- Weber, Thomas J.; Opresko, Lee K.; Waisman, David M.
- Radiation Research, Vol. 172, Issue 1
Annexin A1 is associated with gastric cancer survival and promotes gastric cancer cell invasiveness through the formyl peptide receptor/extracellular signal-regulated kinase/integrin beta-1-binding protein 1 pathway
journal, June 2012
- Cheng, Tsu-Yao; Wu, Ming-Shiang; Lin, Jaw-Town
- Cancer, Vol. 118, Issue 23
Up-regulated Annexin A1 expression in gastrointestinal cancer is associated with cancer invasion and lymph node metastasis
journal, January 2011
- Sato, Yu; Kumamoto, Kensuke; Saito, Katsuharu
- Experimental and Therapeutic Medicine, Vol. 2, Issue 2
Genetic Evidence That Retinaldehyde Dehydrogenase Raldh1 (Aldh1a1) Functions Downstream of Alcohol Dehydrogenase Adh1 in Metabolism of Retinol to Retinoic Acid
journal, September 2003
- Molotkov, Andrei; Duester, Gregg
- Journal of Biological Chemistry, Vol. 278, Issue 38
Dynamics and precision in retinoic acid morphogen gradients
journal, December 2012
- Schilling, Thomas F.; Nie, Qing; Lander, Arthur D.
- Current Opinion in Genetics & Development, Vol. 22, Issue 6
Association of Vitamin A and Carotenoid Intake with Melanoma Risk in a Large Prospective Cohort
journal, June 2012
- Asgari, Maryam M.; Brasky, Theodore M.; White, Emily
- Journal of Investigative Dermatology, Vol. 132, Issue 6
Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis
journal, May 2008
- So, Po-Lin; Fujimoto, Michele A.; Epstein, Ervin H.
- Molecular Cancer Therapeutics, Vol. 7, Issue 5
Induction and prevention of carcinogenesis in rat skin exposed to space radiation
journal, March 2007
- Burns, Fredric J.; (Eric) Tang, Moon-shong; Frenkel, Krystyna
- Radiation and Environmental Biophysics, Vol. 46, Issue 2
Vitamin A and aflatoxin: Effect on liver and colon cancer
journal, January 1983
- Suphakarn, Voranunt S.; Newberne, Paul M.; Goldman, Mark
- Nutrition and Cancer, Vol. 5, Issue 1
Serum retinoic acid, retinol and retinyl palmitate levels in patients with lung cancer
journal, March 2006
- Moulas, Anargyros N.; Gerogianni, Irini C.; Papadopoulos, Dimitrios
- Respirology, Vol. 11, Issue 2
Predicted Rates of Secondary Malignancies From Proton Versus Photon Radiation Therapy for Stage I Seminoma
journal, January 2012
- Simone, Charles B.; Kramer, Kevin; O’Meara, William P.
- International Journal of Radiation Oncology*Biology*Physics, Vol. 82, Issue 1
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
journal, January 2003
- Bakkenist, Christopher J.; Kastan, Michael B.
- Nature, Vol. 421, Issue 6922, p. 499-506
Activation of the Kinase Activity of ATM by Retinoic Acid Is Required for CREB-dependent Differentiation of Neuroblastoma Cells
journal, June 2007
- Fernandes, Norvin D.; Sun, Yingli; Price, Brendan D.
- Journal of Biological Chemistry, Vol. 282, Issue 22
DNA Damage Mediated S and G 2 Checkpoints in Human Embryonal Carcinoma Cells
journal, March 2009
- Wang, XiaoQi; Lui, Vincent C. H.; Poon, Ronnie T. P.
- Stem Cells, Vol. 27, Issue 3
Retinoids, Retinoic Acid Receptors, and Cancer
journal, February 2011
- Tang, Xiao-Han; Gudas, Lorraine J.
- Annual Review of Pathology: Mechanisms of Disease, Vol. 6, Issue 1
Alltrans-retinoic acid induces apoptosis via p38 and caspase pathways in metaplastic Barrett's cells
journal, January 2007
- Hormi-Carver, Kathy; Feagins, Linda A.; Spechler, Stuart J.
- American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 292, Issue 1
Inhibition of Aldehyde Dehydrogenase Expands Hematopoietic Stem Cells with Radioprotective Capacity
journal, January 2010
- Muramoto, Garrett G.; Russell, J. Lauren; Safi, Rachid
- Stem Cells, Vol. 28, Issue 3
Loss of lamin A/C expression in stage II and III colon cancer is associated with disease recurrence
journal, August 2011
- Belt, E. J. Th.; Fijneman, R. J. A.; van den Berg, E. G.
- European Journal of Cancer, Vol. 47, Issue 12
Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest
journal, March 2013
- Singh, Mayank; Hunt, Clayton R.; Pandita, Raj K.
- Molecular and Cellular Biology, Vol. 33, Issue 6
Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations
journal, August 2013
- Yang, Liu; Munck, Martina; Swaminathan, Karthic
- PLoS ONE, Vol. 8, Issue 8
Nuclear Lamins: Laminopathies and Their Role in Premature Ageing
journal, July 2006
- Broers, J. L. V.; Ramaekers, F. C. S.; Bonne, G.
- Physiological Reviews, Vol. 86, Issue 3
Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging
journal, October 2001
- Krtolica, A.; Parrinello, S.; Lockett, S.
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 21
Signaling to p53: Ribosomal Proteins Find Their Way
journal, November 2009
- Zhang, Yanping; Lu, Hua
- Cancer Cell, Vol. 16, Issue 5
Works referencing / citing this record:
The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview
journal, January 2020
- Bellei, Barbara; Caputo, Silvia; Carbone, Anna
- International Journal of Molecular Sciences, Vol. 21, Issue 3
ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis
journal, September 2014
- Weber, Thomas; Magnaldo, Thierry; Xiong, Yijia
- Proteomes, Vol. 2, Issue 3