Treatment of cancer cells with chemotherapeutic drugs results in profound changes in expression of genes encoding aldehyde-metabolizing enzymes

Abstract

Using RNA-seq, RT-qPCR, and bioinformatics we have studied the influence of a wide spectrum of chemotherapeutic drugs on transcription of AKR1B10 , AKR1C1 , ALDH1A1 , and ALDH1A3 genes, which encode the major aldehyde-metabolizing enzymes. The strongest alterations were detected in case of AKR1B10 mRNA that was significantly upregulated in wild type p53 cancer cells, but downregulated in mutant p53 cancer cells. Subsequent experiments demonstrated the significant and consistent decrease in the AKR1B10 mRNA content in sera of colon cancer patients, as compared to sera of healthy donors (p<0.0001, SPE=92.9%, SNE=79.3%, AUC=0.889), which implies that this RNA is a valuable marker for serological diagnosis of colorectal cancer. Moreover, we have found that ALDH1A3 protein is a key inactivator of ROS-generated aldehydes, which is a perspective target for the development of new chemotherapeutic drugs.

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

“…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.…”

The Role of AKR1B10 in Physiology and Pathophysiology

“…Most of the agents upregulate AKR1B10, whereas a phorbol ester 12- O -tetradecanoylphorbol 13-acetate (TPA) down-regulates the expression [ 15 ]. 5-Fluorouracil (5-FU) and oxaliplatin (L-OHP) exhibit opposite effects on the AKR1B10 expression depending on colorectal cancer (CRC) cell lines [ 16 ]. Regulators and signal molecules involved in the modulation of AKR1B10 expression by several agents are also listed in Table 1 .…”

“…Alternatively, expression was induced by these agents in c CRC HCT116 cells having wild-type p53. When the p53 gene in HCT116 cells is knocked-down, 5-FU can no longer induce AKR1B10 [ 16 ]. Thus, p53 protein might act as a switch to determine the direction of AKR1B10 expression, suggesting that the level and status of p53 might be an important factor.…”

“…The expression of AKR1B10 is decreased in patients with CRC and the low expression correlates with poor prognosis and reduced survival [ 16 , 71 , 74 , 75 , 76 ]. It has been suggested that AKR1B10 down-regulation results from mutation of the tumor suppressor p53 gene: Wild-type p53 is a transcriptional activator of AKR1B10, but mutant p53 acts as a repressor [ 16 ]. Recently, Li et al [ 67 ] reported that AKR1B10 expression is negatively regulated by a membrane receptor neuropilin1 (NRP1), which was upregulated in CRC HT29 cells that underwent autophagy following glucose deprivation.…”

Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway

“…Several studies have confirmed the critical role of ALDH1A3 in increasing metastatic behavior and cancer stemness in several cancer types, including breast cancer, lung cancer, colon cancer, glioblastoma, and cholangiocarcinoma [ 16 , 21 , 22 , 23 , 24 , 25 , 26 ]. Kim et al reported that the activation of hypoxia-inducible factor-2α enhances breast cancer stemness [ 22 ].…”