Enzymes of the AKR1B and AKR1C Subfamilies and Uterine Diseases

Abstract

Endometrial and cervical cancers, uterine myoma, and endometriosis are very common uterine diseases. Worldwide, more than 800,000 women are affected annually by gynecological cancers, as a result of which, more than 360,000 die. During their reproductive age, about 70% of women develop uterine myomas and 10–15% suffer from endometriosis. Uterine diseases are associated with aberrant inflammatory responses and concomitant increased production of prostaglandins (PG). They are also related to decreased differentiation, due to low levels of protective progesterone and retinoic acid, and to enhanced proliferation, due to high local concentrations of estrogens. The pathogenesis of these diseases can thus be attributed to disturbed PG, estrogen, and retinoid metabolism and actions. Five human members of the aldo-keto reductase 1B (AKR1B) and 1C (AKR1C) superfamilies, i.e., AKR1B1, AKR1B10, AKR1C1, AKR1C2, and AKR1C3, have roles in these processes and can thus be implicated in uterine diseases. AKR1B1 and AKR1C3 catalyze the formation of PGF2α, which stimulates cell proliferation. AKR1C3 converts PGD2 to 9α,11β-PGF2, and thus counteracts the formation of 15-deoxy-PGJ2, which can activate pro-apoptotic peroxisome-proliferator-activated receptor γ. AKR1B10 catalyzes the reduction of retinal to retinol, and thus lessens the formation of retinoic acid, with potential pro-differentiating actions. The AKR1C1–AKR1C3 enzymes also act as 17-keto- and 20-ketosteroid reductases to varying extents, and are implicated in increased estradiol and decreased progesterone levels. This review comprises an introduction to uterine diseases and AKR1B and AKR1C enzymes, followed by an overview of the current literature on the AKR1B and AKR1C expression in the uterus and in uterine diseases. The potential implications of the AKR1B and AKR1C enzymes in the pathophysiologies are then discussed, followed by conclusions and future perspectives.

Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells

“…The AKR1C isoforms also show broad substrate specificity for other carbonyl compounds including 4-hydroxy-2-nonenal (HNE) [6][7][8], a major product of lipid peroxidation through oxidative stress. For instance, the expression of AKR1C1 is elevated in lung, uterine cervix, and colon cancers [9][10][11], and AKR1C3 is upregulated in leukemia, lung cancers, and carcinomas of hormone-sensitive tissues such as the prostate and mammary gland [9,12,13]. For instance, the expression of AKR1C1 is elevated in lung, uterine cervix, and colon cancers [9][10][11], and AKR1C3 is upregulated in leukemia, lung cancers, and carcinomas of hormone-sensitive tissues such as the prostate and mammary gland [9,12,13].…”

“…Except for liver-specific AKR1C4, the other three isoforms are expressed ubiquitously in normal tissues and overexpressed in cancer cells, although their expression levels differ with the types of cancer and stages of carcinogenesis [5,6]. AKR1C1 and AKR1C3 are also considered to function as regulators for cancer cell multiplication through metabolism of steroids, prostanoids, and isoprenoids [9,14]. AKR1C1 and AKR1C3 are also considered to function as regulators for cancer cell multiplication through metabolism of steroids, prostanoids, and isoprenoids [9,14].…”

New genetic variations discovered in KRAS wild‐type cetuximab resistant chinese colorectal cancer patients

“…UGT2B11, AKR1C1, and mitochondrial glutathione S‐transferase 2 (MGST2) were observed in three GO terms (GO:0006805, GO:0071466, and GO:0009410). Among these genes, AKR1C1 is related to a variety of cancers, including lung cancer, gastric cancer, and cervical cancer 28–32 . One biological process GO term described that CYP4A11 and MGST2 contribute to aldo‐keto reductase (NADP) activity.…”

Aldo‐keto reductases‐mediated cytotoxicity of 2‐deoxyglucose: A novel anticancer mechanism

“…This should restrict the potential undesirable side‐effects of the drugs. Interestingly, another group of enzymes in the family of aldo‐keto reductases, AKR1C1, ‐C2, and ‐C3, are also found to be overexpressed in breast, cervical, and prostate cancers . These enzymes also use NADPH as their cofactor.…”