Evidence that human aldo-keto reductases are regulated by the NRF2-KEAP1 system
| Increased Expression with NRF2 Activator | Decreased Expression with NFE2L2/KEAP1 k/d | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| AKR Gene | AREs in Promotor Region | AREs Based on Positional Matrix | Inducer | Increased RNA | Increased Protein/Activity | Cell Type* | Knockdown Method | Change in RNA | Change in Protein/ Activity | Cell Type* |
| AKR1A1 | 6 | 5 | KEAP1 sh-RNA KEAP1 si-RNANFE2L2 si-RNA | yes no yes | HK-2f HaCaTg HaCaTg | |||||
| AKR1B1 | 1 | 3 | KEAP1 si-RNA KEAP1 sh-RNA KEAP1 si-RNA NFE2L2 si-RNA | yes yes yes yes | yes | MCF-10Aa HK-2f HaCaTg HaCaTg | ||||
| AKR1B10 | 4 | 2 | SFN | yes yes | yes yes | MCF10Aa MCF12Aa | KEAP1 si-RNA KEAP1 si-RNA KEAP1 sh-RNA KEAP1 si-RNA NFE2L2 si-RNA | yes yes yes yes yes | yes yes yes | MCF-10Aa MCF-12Aa HK-2f HaCaTg HaCaTg |
| AKR1B15 | 4 | 5 | ||||||||
| AKR1C1 | 10 | 16 | Ethacrynic acid, SFN, CDDO | yes yes yes yes yes | yes yes yes yes yes | HT29b HepG2c MCF10Aa MCF12Aa HBEC-KTd | KEAP1 si-RNA KEAP1 si-RNA KEAP1 sh-RNA KEAP1 si-RNA NFE2L2 si-RNA CRISPR/Cas9 | yes yes yes yes yes yes | yes yes yes yes yes | MCF-10Aa MCF-12Aa HK-2f HaCaTg HaCaTg HK-2f A-549d |
| AKR1C2 | 15 | 24 | Ethacrynic acid, SFN, CDDO | yes yes yes yes yes | yes yes yes yes yes | HT29b HepG2c MCF10Aa MCF12Aa HBEC-KTd | NFE2L2 KEAP1 si-RNA KEAP1 si-RNA KEAP1 si-RNA KEAP1 sh-RNA NFE2L2 si-RNA CRISPR/Cas9 NFE2L2 | yes yes no yes no yes | yes yes yes no yes | MCF-10Aa MCF-12Aa HaCaTg HK-2f HaCaTg HK-2f A-549d |
| AKR1C3 | 4 | 6 | Ethacrynic acid, SFN, CDDO | yes yes yes yes | yes yes yes yes | HepG2c MCF10Aa MCF12Aa HBEC-KTd | KEAP1 si-RNA KEAP1 si-RNA KEAP1 sh-RNA KEAP1 si-RNA NFE2L2 si-RNA CRISPR/Cas9 NFE2L2 | yes yes yes yes yes yes | yes yes yes | MCF-10Aa MCF-12Aa HK-2f HaCaTg HaCaTg A-549d |
| AKR1C4 | 2 | 2 | ||||||||
| AKR1D1 | 11 | 27 | ||||||||
| AKR1E2 | 6 | 3 | ||||||||
| AKR7A2 | 4 | 9 | Methyl gloxal | yes | yes | HepG2e | NFE2L2 si-RNA | yes | yes | Hep-G2e |
| AKR7A3 | 1 | 4 | ||||||||
aAgyeman et al. (2012).
bCiaccio et al. (1994).
cBurczynski et al. (1999).
dMurray et al. (2019).
eLi et al. (2015).
fJung (2013).
gMacLeod (2009).
*Cell lines: HK-2 (renal carcinoma); MCF-10A, MCF-12A (breast carcinoma); A-549 (lung adenocarcinoma); Hep-G2 (hepatoma cells); HaCaT (human keratinocytes).