Aldose Reductase Inhibition Prevents Hypoxia-induced Increase in Hypoxia-inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF) by Regulating 26 S Proteasome-mediated Protein Degradation in Human Colon Cancer Cells

Abstract

The development of intratumoral hypoxia, a hallmark of rapidly progressing solid tumors, renders tumor cells resistant to chemotherapy and radiation therapy. We have recently shown that inhibition of aldose reductase (AR), an enzyme that catalyzes the reduction of lipid aldehydes and their glutathione conjugates, prevents human colon cancer cell growth in culture as well as in nude mouse xenografts by inhibiting the NF-B-dependent activation of oxidative stress-mediated inflammatory and carcinogenic markers. However, the role of AR in mediating hypoxic stress signals is not known. We therefore investigated the molecular mechanisms by which AR inhibition prevents the hypoxia-induced human colon cancer cells growth and invasion. Our results indicate that AR inhibition by the pharmacological inhibitor fidarestat or ablation by AR-specific siRNA prevents hypoxia-induced proliferation of HT29, SW480, and Caco-2 colon cancer cells. Furthermore, hypoxia-induced increase in the level of HIF-1␣ in colon cancer cells was significantly decreased by AR inhibition. During hypoxic conditions, treatment of HT29 cells with the AR inhibitor fidarestat significantly decreased the expression of vascular endothelial growth factor, a down target of HIF-1␣, at both mRNA and protein levels and also prevented the activation of PI3K/AKT, GSK3␤, Snail, and lysyl oxidase. Furthermore, inhibition of hypoxia-induced HIF-1␣ protein accumulation by AR inhibition was abolished in the presence of MG132, a potent inhibitor of the 26 S proteasome. In addition, AR inhibition also prevented the hypoxiainduced inflammatory molecules such as Cox-2 and PGE2 and expression of extracellular matrix proteins such as MMP2, vimentin, uPAR, and lysyl oxidase 2. In conclusion, our results indicate that AR mediates hypoxic signals, leading to tumor progression and invasion.

PEBP4 gene expression and its significance in invasion and metastasis of non-small cell lung cancer

“…In addition, NF-κB can up-regulate COX-2 expression [30]. PEBP4 overexpression can also up-regulate the expression of COX-2, which induces the expression of angiogenesis-related factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) and promotes tumor angiogenesis through the activation of the hypoxiainducible factor-1 (HIF-1) and inhibition of apoptosis [18,[31][32][33][34]. Furthermore, AKT can promote epithelial-mesenchymal transition, which causes the down-regulation of Ecadherin transcription, a reduction in cell adhesion, and an increase in cell motility and invasiveness [35,36].…”

The Effect of Chemotherapy/Radiotherapy on Cancerous Pattern Recognition by NK Cells

“…Positive effects were observed in breast cancer patients, as treatment with letrozole increased vimentin in tumor tissue [63] and cisplatin-induced residual cancer cells displayed increased expression of vimentin [64]. On the other hand, it was shown that the Aldose reductase inhibitors fidarestat and methotrexate downregulated vimentin in colon cancer cell lines [65,66]. Cancer cell lines demonstrated decreased vimentin expression following treatment with vandetanib [67].…”

Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis

“…Inhibition of aldolase reductase (AR) decreases HIF1α-mediated tumor invasion and growth in CRC [121]. Inhibition of AR activity by fidarestat (Table 1), or by downregulation of AR expression with siRNA, prevents hypoxia-induced proliferation of CRC cells.…”