The effects of
polyunsaturated fatty acids (PUFAs) obtained from the diet on
colorectal cancer have been widely explored. However, controversial results have been obtained about the role played by the lipid peroxidation products of PUFAs, such as 4-hydroxy-nonenal (HNE), in the control of
colon cancer growth. This
aldehyde, indeed, showed both procarcinogenic and protective effects. In an attempt to verify the action of HNE, we studied the effects of a low dose of HNE (1 microM), similar to those "physiologically" found in normal cells and plasma, on
telomerase activity, a key parameter of malignant transformation. Caco-2 cells were exposed to HNE and, paralleling cell growth inhibition, we observed the down-regulation of
telomerase activity and hTERT expression. Similar effects have also been observed in HT-29 cells, in which HNE inhibited cell proliferation,
telomerase activity and hTERT expression, suggesting that the inhibition of
telomerase activity could be a general mechanism involved in the antiproliferative effect exerted by this
aldehyde. Finally, we elucidated the mechanism of hTERT inhibition by HNE. A reduction of GSH content preceded the decrease of
telomerase activity, but this only partially explained the
telomerase activity inhibition. The major mechanism of HNE action seems to be the modulation of expression and activity of
transcription factors belonging to the Myc/Mad/Max network. Since the presence of PUFAs in the diet exposes epithelial colon cells to HNE, this
aldehyde could contribute to cell growth control through the inhibitory action on
telomerase activity and hTERT expression, suggesting a protective effect on colon mucosa.