title: Differential response to α-oxoaldehydes in tamoxifen resistant MCF-7 breast cancer cells.
abstract: Tamoxifen is the standard adjuvant endocrine therapy for estrogen-receptor positive premenopausal breast cancer patients. However, tamoxifen resistance is frequently observed under therapy. A tamoxifen resistant cell line has been generated from the estrogen receptor positive mamma carcinoma cell line MCF-7 and was analyzed for putative differences in the aldehyde defence system and accumulation of advanced glycation end products (AGE). In comparison to wt MCF-7 cells, these tamoxifen resistant cells were more sensitive to the dicarbonyl compounds glyoxal and methylglyoxal and displayed increased caspase activity, p38-MAPK- and IκBα-phosphorylation. However, mRNA accumulation of the aldehyde- and AGE-defence enzymes glyoxalase-1 and -2 (GLO1, GLO2) as well as fructosamine-3-kinase (FN3K) was not significantly altered. Tamoxifen resistant cells contained less free sulfhydryl-groups (glutathione) suggesting that the increased sensitivity towards the dicarbonyls was due to a higher sensitivity towards reactive oxygen species which are associated with dicarbonyl stress. To further analyse, if these data are of more general importance, key experiments were replicated with tamoxifen resistant MCF-7 cell lines from two independent sources. These cell lines were also more sensitive to aldehydes, especially glyoxal, but were different in their cellular signalling responses to the aldehydes. In conclusion, glyoxalases and other aldehyde defence enzymes might represent a promising target for the therapy of tamoxifen resistant breast cancers.
authors.affiliation: Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Nass
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Centre for Basic Medical Research (ZMG), Halle, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Brömme
authors.affiliation: Otto-von-Guericke-University Medical Faculty, Multidimensional Microscopy and Cellular Diagnostics, Magdeburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sevil
authors.initials: S
authors.lastname: Korkmaz
authors.affiliation: Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Saadettin
authors.initials: S
authors.lastname: Sel
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, Halle/Saale, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Hirche
authors.affiliation: German Cancer Research Center DKFZ, Division of Molecular Genome Analysis, Heidelberg, Germany.
authors.forename: Aoife
authors.initials: A
authors.lastname: Ward
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Centre for Basic Medical Research (ZMG), Halle, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Simm
authors.affiliation: German Cancer Research Center DKFZ, Division of Molecular Genome Analysis, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.affiliation: Danish Cancer Society Research Center, Breast Cancer Group, Cell Death and Metabolism, Copenhagen, Denmark.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.affiliation: Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.affiliation: Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kalinski
mesh_terms: D018931:Antineoplastic Agents, Hormonal; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011765:Pyruvaldehyde / Q000494:pharmacology*; D013629:Tamoxifen; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D013629:Tamoxifen; D011765:Pyruvaldehyde; D017853:Phosphotransferases (Alcohol Group Acceptor); C414347:fructosamine-3-kinase; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases