4-hydroxynonenal, a lipid peroxidation product of dietary polyunsaturated fatty acids, has anticarcinogenic properties in colon carcinoma cell lines through the inhibition of telomerase activity.
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.
Pizzimenti
Stefania
S
Department of Medicine and Experimental Oncology, University of Turin, Torino, Italy. stefania.pizzimenti@unito.it
Menegatti
Elisa
E
Berardi
Daniela
D
Toaldo
Cristina
C
Pettazzoni
Piergiorgio
P
Minelli
Rosalba
R
Giglioni
Barbara
B
Cerbone
Angelo
A
Dianzani
Mario U
MU
Ferretti
Carlo
C
Barrera
Giuseppina
G
D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000447:Aldehydes; D019098:Telomerase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal