Expression of the Aldo-Ketoreductases AKR1B1 and AKR1B10 in Human Cancers

Abstract

The American Cancer Society estimates that there will be more than 1.5 million new cases of cancer in 2011, underscoring the need for identification of new therapeutic targets and development of novel cancer therapies. Previous studies have implicated the human aldo-ketoreductases AKR1B1 and AKR1B10 in cancer, and therefore we examined AKR1B1 and AKR1B10 expression across all major human cancer types using the Oncomine cancer gene expression database (Compendia Biosciences, ). Using this database, we found that expression of AKR1B1 and AKR1B10 varies greatly by cancer type and tissue of origin, including agreement with previous reports that AKR1B10 is significantly over-expressed in cancers of the lungs and liver. AKR1B1 is more broadly over-expressed in human cancers than AKR1B10, albeit at a generally lower magnitude. AKR1B1 over-expression was found to be associated with shortened patient survival in acute myelogenous leukemias and multiple myelomas. High AKR1B10 expression tends to predict less aggressive clinical course generally, notably within lung cancers, where it tends to be highly over-expressed compared to normal tissue. These findings suggest that AKR1B1 inhibitors in particular hold great potential as novel cancer therapeutics.

Identification of secreted proteins that reflect autophagy dynamics within tumor cells

“…33 AKR1B1, which exhibited high centrality in our network, forms a direct linkage with ANXA1 (annexin A1), both of which can promote cell proliferation through NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells)-dependent inflammatory pathways. [34][35][36] In summary, our network analysis reveals linkages related to oncogenic and cytokine-mediated cell signaling, providing insights into the functional relevance of autophagy-associated secretions in melanoma.…”

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

“…Although they play a protective role under physiologic situations, their increased activity is considered a pathogenic factor (Alexiou et al, 2009). AKR1B1 is an important mediator of inflammation and diabetic complications (Alexiou et al, 2009;Srivastava et al, 2011;Laffin and Petrash, 2012). AKR1B1 metabolizes reactive aldehydes, like 4-hydroxy-trans-2-nonenal (Ramana et al, 2006), yielding products that perpetuate inflammation .…”

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

“…AKR1B10 can also promote the synthesis of fatty acid/lipid in the gastrointestinal mucosa, facilitating the constant renewal of cryptic cells. Thus, a loss of AKR1B10 would have a detrimental outcome as observed in colon, gastric, head and neck cancers, in which AKR1B10 was down-regulated [50]. Moreover, AKR1B10 shares a high sequence identity (82%) with mouse AKR1B8, and both are mainly expressed in the small intestine and colon, and possess similar efficiency in carbonyl detoxification and lipid biosynthesis [2,51].…”

“…Tolrestat, a well-known ARI [4,62,63], was reported to be the most potent inhibitor for AKR1B10 (1). It inhibited the reductase activity of AKR1B10 with an IC 50 value of approximately 10 nM. In monkey kidney fibroblast COS-1 cells, ectopically expressed AKR1B10 was also completely inhibited by 10 DM tolrestat [4,5].…”

“…Curcuminoids, magnolol (15), honokiol (16) and resveratrol (17) are active substances with higher efficiency for AKR1B10 than for AKR1B1 [24]. Among them, bisdemethoxycurcumin (BDMC, 18) (CN104591987) [98] is the most prominent one, showing an AKR1B10/AKR1B1 selectivity ratio of 85 and a low IC 50 value. The related docking and site-directed mutagenesis analyses suggest that Gln-303, Val-301 and Gln-114 are all essential for curcuminoid potency and selectivity against AKR1B10.…”