Activation of KEAP1/NRF2 stress signaling involved in the molecular basis of hemin-induced cytotoxicity in human pro-erythroid K562 cells

Biochemical Pharmacology
Sofia K Georgiou-Siafis, Asterios S Tsiftsoglou

Abstract

During hemolysis, free heme released from damaged RBCs impairs adjacent cells. As a response, heme induces its metabolic degradation via heme oxygenase-1 (HO-1), activated by NF-E2-related factor 2 (NRF2), the master stress response transcription factor. Heme is well considered a signaling molecule, but how heme does activate NRF2 is not well understood. K562, human pro-erythroid cells responding to hemin (ferric chloride heme), were employed to uncover the major role of Kelch-like ECH-associated protein 1 (KEAP1)/NRF2 stress response signaling, embedded in hemin-induced cytotoxicity (HIC), at ≥50 μM. The intracellular pools of hemin were found to determine the progression from the reversible cell growth inhibition to non-apoptotic cell death. Hemin-induced accumulation of both reactive oxygen species (ROS) and ubiquitinated proteins provoked disturbed cellular proteostasis. Immediate accumulation and nuclear translocation of NRF2 were recorded as defensive adaptation. The NRF2-driven genes encoding glutamate-cysteine ligase (GCLC) and cystine/glutamate antiporter (xCT) were substantially activated. Hemin orchestrated a defensive pathway involving the management of cellular non-protein thiols, via an increase in GSH levels and ...Continue Reading

References

Sep 1, 1981·The Journal of Clinical Investigation·A C Chou, C D Fitch
Oct 28, 1998·Trends in Cell Biology·D H Lee, A L Goldberg
Jul 19, 2002·Cardiovascular Research·Xiao-ming LiuWilliam Durante
Nov 28, 2002·American Journal of Physiology. Renal Physiology·Jawed AlamKarl A Nath
May 3, 2003·Biochemical and Biophysical Research Communications·Muhammad AfzalToru Takeuchi
Nov 13, 2003·Molecular and Cellular Biology·Mi-Kyoung KwakThomas W Kensler
Jan 7, 2004·American Journal of Physiology. Renal Physiology·Luis Gonzalez-MichacaKarl A Nath
Jan 30, 2004·Proceedings of the National Academy of Sciences of the United States of America·Jiying SunKazuhiko Igarashi
Apr 28, 2004·Free Radical Biology & Medicine·Anil K Jaiswal
Dec 2, 2004·Molecular and Cellular Biology·Donna D ZhangMark Hannink
May 27, 2005·Toxicology Letters·Sanjay Kumar, Uday Bandyopadhyay
Jun 30, 2005·The Journal of Biological Chemistry·Fei HongDaniel C Liebler
Mar 4, 2006·Pharmacology & Therapeutics·Asterios S TsiftsoglouLefkothea C Papadopoulou
Oct 1, 1965·The Biochemical Journal·W A Gallagher, W B Elliott
Oct 19, 2007·Nucleic Acids Research·John F ReichardAlvaro Puga
Feb 12, 2008·Current Protocols in Molecular Biology·Susan M AbmayrJerry L Workman
Apr 25, 2008·Current Protocols in Immunology·W Strober
Aug 19, 2008·Free Radical Biology & Medicine·Melissa D LairdKrishnan M Dhandapani
Oct 1, 2010·Science Translational Medicine·Rasmus LarsenMiguel P Soares
May 1, 2001·Current Protocols in Toxicology·P R SinclairJ M Jacobs
Mar 5, 2011·Current Opinion in Hematology·Robert F PaulsonDai-Chen Wu
Jan 17, 2012·American Journal of Physiology. Heart and Circulatory Physiology·Ashlee N HigdonVictor M Darley-Usmar
Jun 19, 2012·Antioxidants & Redox Signaling·Alexandria LauDonna D Zhang
Aug 9, 2012·Proceedings of the National Academy of Sciences of the United States of America·Keiko TaguchiMasayuki Yamamoto
Dec 12, 2012·Biochemical Pharmacology·Holly K BryanB Kevin Park
Mar 9, 2013·Cold Spring Harbor Perspectives in Medicine·Harry A Dailey, Peter N Meissner
Aug 13, 2013·Oxidative Medicine and Cellular Longevity·Hye-Youn Cho

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Citations

May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ipek SüntarLuciano Saso
Oct 8, 2021·Journal of Cellular Physiology·Vasiliki-Dimitra C TsolakiAsterios S Tsiftsoglou

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