NRF2 as a determinant of cellular resistance in retinoic acid cytotoxicity.
Clinical use of retinoic acids (RA) is hindered by toxicity possibly related to oxidative stress. Recently, RA at relatively low concentrations was shown to inhibit NRF2 and the expression of its target antioxidative genes. This raises the possibility that RA toxicity may result from cellular inability to cope with resultant oxidative stress. Using in vitro cell and in vivo mouse models, we report that RA, specifically all-trans-RA (atRA) at concentrations implicated in toxicity, can activate NRF2 and induce NRF2 target genes, particularly the subunits of the rate-limiting enzyme of glutathione biosynthesis, glutamate cysteine ligase (GCLM/GCLC). RNA interference-mediated silencing of NRF2, but not of retinoid X receptor-alpha and -beta, reduced basal and atRA-induced GCLM/GCLC gene expression. Moreover, RA increased nuclear accumulation of NRF2, antioxidant response element (ARE) reporter activity, and NRF2 occupancy at AREs. 4-Hydroxynonenal, a lipid peroxidation product, was increased by RA. Inhibition of MEK1/ERK mitogen-activated protein kinases significantly suppressed atRA-induced NRF2 activation and ARE-regulated gene expression, reducing cell resistance against toxic concentrations of RA. NRF2-silenced cells were vulnerable to atRA-induced mitochondrial toxicity and apoptosis. In conclusion, toxic RA activates NRF2, thereby triggering an adaptive response against the resultant oxidative stress. NRF2 enhancement as a therapeutic target of retinoid toxicity awaits further investigation.
Division of Clinical Pharmacology and Toxicology, Physiology and Experimental Medicine Program, The Research Institute, The Hospital for Sick Children, Department of Pediatrics and Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
Kah Poh
KP
Tan
Kazuhiro
K
Kosuge
Mingdong
M
Yang
Shinya
S
Ito
D000230:Adenocarcinoma / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation; D008113:Liver Neoplasms / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020218:Response Elements; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D049230:Retinoid X Receptor beta / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D000447:Aldehydes; D000970:Antineoplastic Agents; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D014212:Tretinoin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D005721:Glutamate-Cysteine Ligase; C027576:4-hydroxy-2-nonenal