Differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chemopreventive compounds in HepG2 human hepatoma cells.
Nuclear factor-E2-related factor 2 (Nrf2) is known as a key regulator of ARE-mediated gene expression and the induction of Phase II detoxifying enzymes and antioxidant enzymes, which is also a common property of many chemopreventive agents. In the present study, we investigated the regulatory role of different chemopreventive agents including sulforaphane (SUL), allyl isothiocyanate (AITC), indole-3-carbinol (I3C), and parthenolide (PTL), in the expression and degradation of Nrf2 and the induction of the antioxidant enzyme HO-1. SUL strongly induced Nrf2 protein expression and ARE-mediated transcription activation, retarded degradation of Nrf2 through inhibiting Keap1, and thereby activating the transcriptional expression of HO-1. AITC was also a potent inducer of Nrf2 protein expression, ARE-reporter gene and HO-1 but had little effect on delaying the degradation of Nrf2 protein. Although PTL and I3C could induce AREreporter gene expression and Nrf2 to some extent, they were not as potent as SUL and AITC. However, PTL dramatically induced the HO-1 expression, which was comparable to SUL, while I3C had no effect. In addition, when treated with SUL and PTL, inhibition of proteasome by MG132 did not cause additional accumulation of Nrf2, suggesting the involvement of other degradation mechanism(s) in the presence of these compounds such as SUL and PTL. In summary, the results of our current study indicated that different chemopreventive compounds have different regulatory properties on the accumulation and degradation of Nrf2 as well as the induction of cellular antioxidant enzyme HO-1.
Jeong
Woo-Sik
WS
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, NJ 08854, USA.
Keum
Young-Sam
YS
Chen
Chi
C
Jain
Mohit R
MR
Shen
Guoxiang
G
Kim
Jung-Hwan
JH
Li
Wenge
W
Kong
Ah-Ng Tony
AN
D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D011506:Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology; D013454:Sulfoxides; D013861:Thiocyanates / Q000737:chemistry / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation
D016588:Anticarcinogenic Agents; D004268:DNA-Binding Proteins; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D017879:Isothiocyanates; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011506:Proteins; D012717:Sesquiterpenes; D013454:Sulfoxides; D013861:Thiocyanates; D015534:Trans-Activators; C002669:parthenolide; C004471:allyl isothiocyanate; C016517:indole-3-carbinol; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C016766:sulforaphane