4-hydroxy-2-nonenal and Carcinoma

The antioxidant transcription factor NFE2-related factor 2 (Nrf2), encoded by NFE2L2, has been implicated as mediator of thyroid cancer cell line resistance to proteasome inhibitors. However, the activity status of the Nrf2 pathway in human thyroid cancer remains unknown.. The aims of this study were assessment of the activity status of the Nrf2 pathway in papillary thyroid carcinoma (PTC) and investigation of its role(s) in antioxidant transcriptional responses and viability of cancer cells.. We conducted retrospective immunohistochemical analyses of PTC specimens, adjacent normal tissue, and benign lesions; assays of viability and gene expression in the PTC cell lines K1 and TPC-1 after genetic/pharmacological manipulation of Nrf2; and DNA sequencing at an academic medical center.. The study included 42 PTC and 42 benign lesions (24 adenomas and 18 nodular hyperplasias).. We assessed the abundance of Nrf2, Nqo1, Keap1, and 4HNE; cell line viability and mRNA expression of Nrf2, Nqo1, and Trdx1; and the sequence of NFE2L2, KEAP1, and BRAF.. Nrf2 and its target Nqo1 were undetectable in normal tissue; their levels were significantly higher in PTC than in benign lesions (P < .0001 and P = .024, respectively). The Nrf2 inhibitor Keap1 was variably abundant in PTC, and its levels did not correlate with Nrf2 (P = .37), arguing against decreased levels as the mechanism for Nrf2 activation. The oxidized lipid 4HNE was more abundant in PTC than normal tissue (P < .001), indicating oxidative stress. Nrf2 mediated transcriptional antioxidant responses in both the PTC cell lines K1 and TPC-1 and in the nontransformed cell line TAD2, but it conferred a viability advantage specifically in the PTC cell lines.. The high activity of Nrf2 in PTC warrants further exploration of this pathway's potential diagnostic, prognostic, and/or therapeutic utility in PTC.

Topics: Aldehydes; Antioxidants; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Survival; Humans; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Oxidative Stress; Retrospective Studies; Signal Transduction; Thyroid Cancer, Papillary; Thyroid Neoplasms; Transcription, Genetic

The oxidation of polyunsaturated fatty acids during oxidative stress gives rise to a series of toxic alpha,beta-unsaturated aldehydes, including the electrophile 4-hydroxy-2-nonenal (4-HNE) and the related aldehydes, 4-hydroperoxy-2-nonenal (4-HPNE) and 4-oxo-2-nonenal (4-ONE). We synthesized these compounds, as well as the resolved enantiomers of 4-HNE, and compared their toxicities and apoptotic responses in the human colorectal cancer cell line RKO. All of these molecules execute similar death responses at comparable doses over almost identical time frames in RKO cells. The apoptotic response induced by 4-HPNE, 4-ONE, and 4-HNE enantiomers involves activation of caspases, proteolysis of downstream caspase targets, and nucleosomal DNA fragmentation. The results presented herein suggest that these molecules commonly activate certain signaling pathways that control cell death irrespective of their reactive properties.

Topics: Aldehydes; Apoptosis; Carcinoma; Colorectal Neoplasms; DNA Damage; Humans; Lipid Peroxidation; Proteins; Tumor Cells, Cultured