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akr1b10

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Official Full Name
aldo-keto reductase family 1, member B10 (aldose reductase)
Background
This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. This member can efficiently reduce aliphatic and aromatic aldehydes, and it is less active on hexoses. It is highly expressed in adrenal gland, small intestine, and colon, and may play an important role in liver carcinogenesis. [provided by RefSeq, Jul 2008]
Synonyms
AKR1B10; aldo-keto reductase family 1, member B10 (aldose reductase); HIS; HSI; ARL1; ARL-1; ALDRLn; AKR1B11; AKR1B12; aldo-keto reductase family 1 member B10; ARP; hARP; SI reductase; aldose reductase-like 1; small intestine reductase; aldose reductase-like peptide; aldose reductase-related protein; aldo-keto reductase family 1, member B11 (aldose reductase-like); aldo keto reductase family 1; member B11 (aldose reductase like); aldose reductase like 1; aldose reductase like peptide; aldose reductase related protein; ARL 1; MGC14103; HIS, HSI, ARL1, ARL-1, ALDRLn, AKR1B11, AKR1B12; AKR

Aldo-keto reductase family1, member10 (AKR1B10) is also known as aldose reductase-like protein -1(ARL-1), derived from the AKR1B family. AKR1B10 has >70% homology to the AKR1B1 amino acid sequence. However, unlike AKR1B1, AKR1B10 is not expressed in all tissues of human body. In normal human tissues, AKR1B10 protein is mainly expressed in the small intestine and colon, and is expressed at low levels in the liver, prostate, testis, and thymus. AKR1B10 has a detoxifying function mainly because it can reduce toxic aldehydes and ketones. In addition, AKR1B10 also forms a protein complex by binding to acetyl-CoA carboxylase alpha (ACCA) in order to prevent ACCA degradation and regulate lipid synthesis.

AKR1B10 and Cancer

AKRs have a wide range of substrate specificity and species distribution, which may be involved in different biological processes in different organisms, including carbonyl detoxification, osmotic adjustment, hormone metabolism, lipid synthesis, diabetic complications, tumor formation, etc. AKR1B10 Overexpression in humans was first discovered in liver cancer, and some studies on the mRNA and protein expression levels of AKR1B10 in liver cancer also indicated its high expression in liver cancer.

Ohashi et al. compared the mRNA content of H1299 cells in overexpressed and control groups of p53 family members by cDNA microarray analysis. It was determined that AKR1B10 was identified as a direct target of the p53 family. In addition, studies have found that the expression of AKR1B10 in colorectal cancer and adenoma is significantly reduced compared to normal colon tissue. AKR1B10 gene knockdown significantly inhibited p53-induced apoptosis of colorectal cancer cells, while overexpression of AKR1B10 enhanced p53-induced apoptosis and inhibited tumor proliferation. In addition, low expression of AKR1B10 in colon cancer patients is associated with decreased survival and poor prognosis. These results indicate that decreased expression of AKR1B10 may disrupt the tumor suppressor function of p53, resulting in decreased survival in patients with colorectal cancer. In conclusion, AKR1B10 may be a new prognostic predictor of colorectal cancer and a new therapeutic target.

AKR1B10 Figure 1. AKR1B10, a transcriptional target of p53, is downregulated in colorectal cancers associated with poor prognosis. (Ohashi, et al. 2013)

A study found that AKR1B10 was highly expressed in 84.4% of lung squamous cell carcinomas and 29.2% of lung adenocarcinoma tissues, but it was not found in normal lung tissues. AKR1B10 is highly expressed in 20% of cervical cancer tissues and 15.8% of endometrial cancer tissues. Further studies suggest that postoperative recurrence of cervical cancer and keratinization of squamous cell carcinoma are closely related to high expression of AKR1B10. AKR1B10 is highly expressed in 70% of pancreatic cancer and pancreatic intraepithelial neoplasia. In some precancerous lesions, such as the erosion of the esophagus and Barrett's epithelium, high expression of AKR1B10 is also found.

The expression of AKR1B10 is closely related to tumor chemotherapy resistance. AKR1B10 can induce tumor cell resistance to daunorubicin and demethoxydaunorubicin by reducing the C13 carbonyl group. Many of currently used tumor chemotherapy drugs themselves contain aldehyde and ketone groups, such as anthracyclines such as daunorubicin. Adriamycin is one of the commonly used drugs for clinical chemotherapy in breast cancer. The doxorubicin and the daunorubicin are both anthracyclines and their carbonyl groups in the side chain may be reduced by AKR1B10 to affect their antitumor activity. AKR1B10 is a very important cytoprotective protein. It not only promotes lipid synthesis, but also eliminates toxic aldehydes and ketones in cells, thereby promoting cell growth and survival. AKR1B10 plays an important role in the growth of non-small cell lung cancer cells and tumors.

AKR1B10 Inhibitor

Since AKR1B1 and AKR1B10 have more than 71% similarity of the identical amino acid sequence, causing similarity in activity and selectivity of the inhibitors. As a result,many AKR1B1 inhibitors also exhibit inhibition of the AKR1B10.

At present, there are many studies on the specific expression of AKR1B10 in tumors and the resistance to chemotherapeutic drugs, but the specific mechanism is still unclear. AKR1B10 inhibitors can affect the sensitivity of tumor cells to chemotherapeutic drugs. This can provide new ways to improve the efficacy of cancer chemotherapy. With the deepening of research on AKR1B10 and its inhibitors, finding efficient and selective AKR1B10 inhibitors will bring new hope for the diagnosis and treatment of tumors.

Zemanova et al. examined 40 different phenolic resin and a compound for inhibitory activity of alkaloids of AKR1B10. Wherein apigenin 35 (IC50 = 6.6 μmol·L-1), luteolin compound 36 (IC50 = 9.2 μmol·L-1) and 7-hydroxy flavone compound 37 (IC50 = 8.3 μmol·L-1) having superior inhibitory activity, Wei et al. found that a number of steroidal compounds (43 to 46) have inhibitory activity against AKR1B10, wherein the compound 44a strongest inhibition (IC50 = 0.50 μmol·L-1). Compound 43a is the most selective Strong (AKR1B1/AKR1B10=195). Cousido-Siah et al. found that sulindac is a potent metabolic precursor of NSAID sulindac sulfide, which is mediated by the involvement of AKR1B10 in a COX-independent mechanism, making it highly anti-tumor.

The appropriate structural modification based on the nucleus of AKR1B10 inhibitor can affect its inhibitory activity and selectivity. It is also found to have a certain inhibitory effect on the specificity of AKR1B1. In addition, the mechanism of action of AKR1B10 and its inhibitors is still unclear, and further in-depth research and exploration is needed.

References:

  1. Ohashi, T., Idogawa, M., Sasaki, Y., Suzuki, H., & Tokino, T. (2013). Akr1b10, a transcriptional target of p53, is downregulated in colorectal cancers associated with poor prognosis. Molecular Cancer Research Mcr, 11(12), 1554.
  2. Yao, H. B., Xu, Y., Chen, L. G., Guan, T. P., Ma, Y. Y., & Tao, H. Q., et al. (2013). [expression of aldo-keto reductase family 1 member b10 in gastric cancer tissues and its clinical significance]. Chinese journal of gastrointestinal surgery, 16(2), 183.
  3. Hashimoto, Y., Imanishi, K., Tokui, N., Okamoto, T., Okamoto, A., & Hatakeyama, S., et al. (2013). Carboplatin–gemcitabine combination chemotherapy upregulates akr1b10 expression in bladder cancer. International Journal of Clinical Oncology, 18(1), 177-182.
  4. Zemanova, L., Hofman, J., Novotna, E., Musilek, K., Lundova, T., & Havrankova, J., et al. (2015). Flavones inhibit the activity of akr1b10, a promising therapeutic target for cancer treatment. Journal of Natural Products, 78(11), 2666-74.
  5. Zhang, W., Wang, L., Zhang, L., Chen, W., Chen, X., & Xie, M., et al. (2014). Synthesis and biological evaluation of steroidal derivatives as selective inhibitors of akr1b10. Steroids, 86(4), 39-44.
  6. Cousido-Siah, A., Ruiz, F. X., Crespo, I., Porté, S., Mitschler, A., & Parés, X., et al. (2015). Structural analysis of sulindac as an inhibitor of aldose reductase and akr1b10. Chemico-Biological Interactions, 234, 290-296.