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AKR1B10, a Transcriptional Target of p53, Is Downregulated in Colorectal Cancers Associated with Poor Prognosis.

Ohashi T, Idogawa M, Sasaki Y, Suzuki H, Tokino T.

Mol Cancer Res. 2013 ;11(12):1554-63.

S1W17, Chuo-Ku, Sapporo 060-8556, Japan. [email protected]

Abstract

p53 is one of the most important tumor suppressor genes, and it is frequently inactivated in various cancers. p53 modulates various cellular functions, such as apoptosis and cell-cycle arrest via transcriptional regulation. Recently, p53 has been reported to be involved in a wide range of cellular metabolic pathways, including glycolysis, oxidative phosphorylation, glutaminolysis, and the antioxidant response. To understand the functional mechanism of p53, it is important to find out the direct transcriptional targets of p53. In this study, aldo-keto reductase family 1, member B10 (AKR1B10) was identified as a direct target of the p53 family by cDNA microarray analysis after comparing the mRNA expression of control and H1299 cells that overexpressed with p53 family members. In addition, we found that the expression of AKR1B10 was significantly decreased incolorectal cancers and adenomas as compared with normal colon tissues. Knockdown of AKR1B10 significantly inhibited p53-induced apoptosis incolorectal cancer cells, whereas the overexpression of AKR1B10 enhanced p53-induced apoptosis and inhibited tumor proliferation in vivo. Furthermore, low expression of AKR1B10 in colon cancer patients was correlated with decreased survival and poor prognosis. These results suggest that decreased expression of AKR1B10 could disrupt the tumor suppressive function of p53, which result in decreased survival in colorectal cancer patients. In summary, AKR1B10 may be a novel prognostic predictor and a novel therapeutic target for colorectal cancer. Implications: AKR1B10, atranscriptional target of p53, is also a novel prognostic and therapeutic molecule in colorectal cancer. Mol Cancer Res; 11(12); 1554-63. ©2013 AACR.

 

 

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Additional Information

 

p53 is one of the most important tumor suppressor genes and is frequently inactivated in various cancers, as a direct result of mutations in the p53 gene. Therefore, many studies have sought to identify target genes of p53 and its family members because these proteins execute diverse functions, mainly through transcriptional regulation. To identify direct targets of p53 family members, we compared mRNA expression in H1299 cells overexpressing p53 family members and control cells through cDNA microarray and identified aldo-keto reductase family 1, member B10 (AKR1B10) as a direct target of the p53 family. AKR1B10 is a member of the aldo-keto reductase (AKR) superfamily, which is comprised of several enzymes that catalyze redox transformations involved in biosynthesis, intermediary metabolism and detoxification. One characteristic feature of AKRs is their ability to catalyze aldehyde or ketone reduction. In addition, the amino acid sequence of AKR1B10 is 71% identical to that of aldose reductase, and this enzyme exhibits substrate specificity and inhibitor sensitivity similar to aldose reductase. In contrast to ubiquitously expressed AKRs, AKR1B10 is mainly expressed in normal small intestine and colon, which suggests that the physiological function of AKR1B10 is specifically required in intestinal tissues. We showed that knockdown of AKR1B10 significantly inhibited p53-induced apoptosis in colorectal cancer cells. The expression of AKR1B10 was decreased in most colorectal cancers, while the normal function of p53 is preserved in approximately one-half of colorectal cancers. Furthermore, low expression of AKR1B10 in colon cancers was correlated with decreased survival and poor prognosis. These results indicate that the inhibition of p53-induced apoptosis, resulting from the suppression of AKR1B10, contributes to the decreased survival rate of patients with colon cancer. AKR1B10 expression may be useful for prognostic prediction and that interventions focused on metabolic pathways involving AKR1B10 may represent novel therapeutic approaches for colorectal cancers.

AKR1B10, a Transcriptional Target of p53, Is Downregulated in Colorectal Cancers Associated with Poor Prognosis