Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis

Wright, Aaron T.; Magnaldo, Thierry; Sontag, Ryan L.; Anderson, Lindsey N.; Sadler, Natalie C.; Piehowski, Paul D.; Gache, Yannick; Weber, Thomas J.

doi:10.1002/mc.22115

Title: Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis

Journal Article · Wed Nov 27 00:00:00 EST 2013 · Molecular Carcinogenesis

DOI:https://doi.org/10.1002/mc.22115· OSTI ID:1203899

Wright, Aaron T. ^[1]; Magnaldo, Thierry ^[2]; Sontag, Ryan L. ^[3]; Anderson, Lindsey N. ^[1]; Sadler, Natalie C. ^[1]; Piehowski, Paul D. ^[1]; Gache, Yannick ^[4]; Weber, Thomas J. ^[5]

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

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.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830; 8P41GM103493-10; ET9-551; SFI201212055859

OSTI ID:: 1203899

Report Number(s):: PNNL-SA-95210; 47292; KP1602020

Journal Information:: Molecular Carcinogenesis, Vol. 54, Issue 6; ISSN 0899-1987

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 7 works

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