Aldo-keto reductase family 1 member B10 promotes cell survival by regulating lipid synthesis and eliminating carbonyls.
Aldo-keto reductase family 1 member B10 (AKR1B10) is primarily expressed in the normal human colon and small intestine but overexpressed in liver and lung cancer. Our previous studies have shown that AKR1B10 mediates the ubiquitin-dependent degradation of acetyl-CoA carboxylase-alpha. In this study, we demonstrate that AKR1B10 is critical to cell survival. In human colon carcinoma cells (HCT-8) and lung carcinoma cells (NCI-H460), small-interfering RNA-induced AKR1B10 silencing resulted in caspase-3-mediated apoptosis. In these cells, the total and subspecies of cellular lipids, particularly of phospholipids, were decreased by more than 50%, concomitant with 2-3-fold increase in reactive oxygen species, mitochondrial cytochrome c efflux, and caspase-3 cleavage. AKR1B10 silencing also increased the levels of alpha,beta-unsaturated carbonyls, leading to the 2-3-fold increase of cellular lipid peroxides. Supplementing the HCT-8 cells with palmitic acid (80 mum), the end product of fatty acid synthesis, partially rescued the apoptosis induced by AKR1B10 silencing, whereas exposing the HCT-8 cells to epalrestat, an AKR1B10 inhibitor, led to more than 2-fold elevation of the intracellular lipid peroxides, resulting in apoptosis. These data suggest that AKR1B10 affects cell survival through modulating lipid synthesis, mitochondrial function, and oxidative status, as well as carbonyl levels, being an important cell survival protein.
Wang
Chun
C
Department of Medical Microbiology, SimmonsCooper Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA.
Yan
Ruilan
R
Luo
Dixian
D
Watabe
Kounosuke
K
Liao
Duan-Fang
DF
Cao
Deliang
D
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis*; D008315:Malondialdehyde / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D019308:Palmitic Acid / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012236:Rhodanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology
D000447:Aldehydes; D004791:Enzyme Inhibitors; D008054:Lipid Peroxides; D008055:Lipids; D017382:Reactive Oxygen Species; D053778:Thiazolidines; D019308:Palmitic Acid; C038131:epalrestat; D008315:Malondialdehyde; D012236:Rhodanine; D045304:Cytochromes c; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C027576:4-hydroxy-2-nonenal