Phorbol ester up-regulates aldose reductase expression in A549 cells: a potential role for aldose reductase in cell cycle modulation

Abstract

Over-expression of aldose reductase (AR) has been observed in many cancer cells. To clarify the role of AR in tumor cells, we investigated the pathways mediating expression of the AR gene induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent tumor promoter. In A549 human lung adenocarcinoma cells, TPA elicited a dose- and time-dependent increase in AR mRNA level with an elevated enzyme activity. The TPA-induced increase in mRNA level and promoter activity of the AR gene was significantly attenuated in the presence of an inhibitor of protein kinase C, tyrosine kinase, or nuclear factor kappaB (NF-kappaB). TPA augmented the NF-kappaB-dependent gene transcription, indicating the involvement of NF-kappaB in this regulation. Accumulation of TPA-treated cells in S phase was almost completely abolished in the presence of ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate, an AR inhibitor. Taken together, TPA augmented the promoter activity of the AR gene via the activation of protein kinase and NF-kappaB. The inhibition of AR may assist in the chemotherapy of malignant tumors by suppressing the rapid growth of cancer cells.

Aldose Reductase Regulates Growth Factor-Induced Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Colon Cancer Cells

“…4). Our results showing the arrest of Caco-2 cells at S phase by AR inhibition are similar to human lung adenocarcinoma cells (43).…”

“…These observations suggest that AR is a growth-responsive protein, which may be involved in facilitating metabolic changes that accompany growth of colon cancer cells. Consistent with this view, other investigators (23,40,42,43) have shown that the expression of AR is minimal in quiescent cells and is robust under hyperglycemic and growth factor-induced oxidative stress. Prevention of growth factor-induced PGE 2 production and cell growth by pharmacologic inhibition of AR by sorbinil was further confirmed by ablation of AR (Fig.…”

Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders

“…Because sorbitol and myo-inositol are structurally similar, the depletion of myo-inositol appears to be due in part to the inhibition of its uptake in cells accumulating sorbitol [87]. Furthermore, it has recently been demonstrated that stimulation of PKC by phorbol esters up-regulates AKR1B1 indicating that some of the injurious effects of PKC activation may be mediated by AKR1B1 [88]. Accumulating evidence suggests that effects of non-enzymatic glycosylation and AKR1B1 are inter-related [89,90].…”

A JNK1/AP-1–Dependent, COX-2 Induction Is Implicated in 12-O-Tetradecanoylphorbol-13-Acetate–Induced Cell Transformation through Regulating Cell Cycle Progression

“…TPA has been reported to promote cell proliferation and cell cycle progression in A549 cells (22). COX-2 is associated with cell proliferation and growth in some cancerous conditions (23), and the inhibitors of COX-2 are able to interfere cell cycle progression by regulating the cell cycle -related proteins, such as cyclins (24), which are critical for oncogenic transformation (21).…”