The Role of AKR1B10 in Physiology and Pathophysiology

Endo, Shunsuke; Matsunaga, Toshiyuki; Nishinaka, Toru

doi:10.3390/metabo11060332

Cited by 51 publications

(40 citation statements)

References 173 publications

(290 reference statements)

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“…Although initially surprising, the reduced expression of AKR1B10 in the tumours is consistent with the previously reported decreased AKR1B10 expression in human colorectal cancer [37,38] and the decrease in the mRNA levels for AKR1B10 in sera of colon cancer patients in comparison with sera of healthy donors [39]. In addition to Nrf2, AKR1B10 is transcriptionally regulated by p53 [37,40], in agreement with the upregulation of the AKR1B10 mRNA by chemotherapeutic agents in normal diploid cells and in cancer cells expressing wild type p53, and its downregulation in cancer cells harbouring mutant p53 [39]. Because p53 is commonly mutated in colorectal cancer [41], the observed downregulation of AKR1B10 in our study is most likely due to loss of the normal function of p53.…”

Section: Discussionsupporting

confidence: 88%

Pirin, an Nrf2-Regulated Protein, Is Overexpressed in Human Colorectal Tumors

et al. 2022

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The evolutionary conserved non-heme Fe-containing protein pirin has been implicated as an important factor in cell proliferation, migration, invasion, and tumour progression of melanoma, breast, lung, cervical, prostate, and oral cancers. Here we found that pirin is overexpressed in human colorectal cancer in comparison with matched normal tissue. The overexpression of pirin correlates with activation of transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and increased expression of the classical Nrf2 target NAD(P)H:quinone oxidoreductase 1 (NQO1), but interestingly and unexpectedly, not with expression of the aldo-keto reductase (AKR) family members AKR1B10 and AKR1C1, which are considered to be the most overexpressed genes in response to Nrf2 activation in humans. Using pharmacologic and genetic approaches to either downregulate or upregulate Nrf2, we show that pirin is regulated by Nrf2 in human and mouse cells and in the mouse colon in vivo. The small molecule pirin inhibitor TPhA decreased the viability of human colorectal cancer (DLD1) cells, but this decrease was independent of the levels of pirin. Our study demonstrates the Nrf2-dependent regulation of pirin and encourages the pursuit for specific pirin inhibitors.

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Section: Discussionsupporting

confidence: 88%

Pirin, an Nrf2-Regulated Protein, Is Overexpressed in Human Colorectal Tumors

et al. 2022

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“…As explained above, AKR1B10 is in fact the closest enzyme to AR (sharing 71% amino acid identity), and we and others surmised that the lack of selectivity of ARIs could be a relevant factor contributing to their failure as pharmacological drugs [10][11][12]. Furthermore, AKR1B10 is now established as a promising cancer target (except for gastric cancers, where it is downregulated) [12,16], and the ubiquitously expressed AR can represent a problematic off-target, given its overall similarity with AKR1B10. Next, we will provide an overview of the different AKR1B10 inhibitor types in the context of the available three-dimensional structures of AKR1B10 deposited in the PDB (Table A1).…”

Section: Akr1b10 Inhibition Strategiesmentioning

confidence: 84%

“…To note that an exhaustive listing and description of AKR1B10 inhibitors is beyond the scope of this review. We refer the reader to the revisions of Huang et al [17] and, more recently, Endo et al [16,18] for further details.…”

Section: Akr1b10 Inhibition Strategiesmentioning

confidence: 99%

“…AKR1B10 has a key role in protecting the GI tract from lipid peroxides and reactive aldehydes, and its expression is decreased in GI cancers [2,16]. Thus, finding small molecule activators of its activity could potentially be beneficial in both precancerous and cancerous lesions of the GI tract in which AKR1B10 downregulation has been observed.…”

Section: Potential For Akr1b10 Catalytic Activatorsmentioning

confidence: 99%

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Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition

2021

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Human aldo-keto reductase 1B10 (AKR1B10) is overexpressed in many cancer types and is involved in chemoresistance. This makes AKR1B10 to be an interesting drug target and thus many enzyme inhibitors have been investigated. High-resolution crystallographic structures of AKR1B10 with various reversible inhibitors were deeply analyzed and compared to those of analogous complexes with aldose reductase (AR). In both enzymes, the active site included an anion-binding pocket and, in some cases, inhibitor binding caused the opening of a transient specificity pocket. Different structural conformers were revealed upon inhibitor binding, emphasizing the importance of the highly variable loops, which participate in the transient opening of additional binding subpockets. Two key differences between AKR1B10 and AR were observed regarding the role of external loops in inhibitor binding. The first corresponded to the alternative conformation of Trp112 (Trp111 in AR). The second difference dealt with loop A mobility, which defined a larger and more loosely packed subpocket in AKR1B10. From this analysis, the general features that a selective AKR1B10 inhibitor should comply with are the following: an anchoring moiety to the anion-binding pocket, keeping Trp112 in its native conformation (AKR1B10-like), and not opening the specificity pocket in AR.

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“…However, the differences were reversed in tumor tissues. These findings attracted the attention of researchers and resulted in a differential effect of the targeted inhibition of AKR1B10 on tumor cells [ 9 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

AKR1B10 inhibits the proliferation and migration of gastric cancer via regulating epithelial-mesenchymal transition

Shao

Wu²,

et al. 2021

Aging

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Gastric cancer (GC) is a common malignancy around the world with a poor prognosis. Aldo-keto reductase family 1 member B10 (AKR1B10) is indispensable to cancer development and progression, which has served as a diagnostic biomarker for tumors. In our study, we demonstrated that the expression of AKR1B10 in GC tissues was significantly lower compared with normal gastric tissues. Subgroup analysis showed that, according to the clinic-pathological factors, the effect of the AKR1B10 expression level on the prognosis of GC patients was significantly different. Moreover, reduced expression of AKR1B10 promoted the ability of GC cells in proliferation and migration. Furthermore, increased AKR1B10 levels resulted in the opposite trend in vitro . Moreover, AKR1B10 was correlated with epithelial-mesenchymal transition (EMT) in a significant way. In vivo experiment, knockdown of AKR1B10 promoted the growth of tumor, increased Vimentin, and E-cadherin significantly. In summary, AKR1B10 is considered as a tumor suppressor in GC and is a promising therapeutic target.

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The Role of AKR1B10 in Physiology and Pathophysiology

Cited by 51 publications

References 173 publications

Pirin, an Nrf2-Regulated Protein, Is Overexpressed in Human Colorectal Tumors

Pirin, an Nrf2-Regulated Protein, Is Overexpressed in Human Colorectal Tumors

Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition

AKR1B10 inhibits the proliferation and migration of gastric cancer via regulating epithelial-mesenchymal transition

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