Polyunsaturated fatty acids inhibit telomerase activity in DLD-1 human colorectal adenocarcinoma cells: a dual mechanism approach.
As high telomerase activity is detected in most cancer cells, telomerase represents a promising cancer therapeutic target. We investigated the inhibitory effect of various fatty acids on telomerase, with particular emphasis on those with antitumor properties, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). To evaluate the direct effect of fatty acids on telomerase, cell lysates of DLD-1 human colorectal adenocarcinoma cells were mixed with sample fatty acids, and the telomerase activity was determined. Saturated fatty acids and trans-fatty acids showed very weak or no inhibition of telomerase. In contrast, cis-unsaturated fatty acids significantly inhibited the enzyme, and the inhibitory potency was elevated with an increase in the number of double bonds. Accordingly, polyunsaturated fatty acids (PUFAs), like EPA and DHA, appeared to be powerful telomerase inhibitors. To assess the transcriptional effect, DLD-1 cells were cultured in the presence of sample fatty acids, and telomerase activity and gene expression were subsequently evaluated. Culturing DLD-1 cells with either EPA or DHA resulted in a remarkable decrease in telomerase activity. EPA and DHA inhibited telomerase by down-regulating human telomerase reverse transcriptase (hTERT) and c-myc expression via protein kinase C inhibition. These results indicate that PUFAs can directly inhibit the enzymatic activity of telomerase as well as modulate the telomerase at the transcriptional level.
Eitsuka
Takahiro
T
Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori Amamiyamachi, Sendai 981-8555, Japan.
Nakagawa
Kiyotaka
K
Suzuki
Toshihide
T
Miyazawa
Teruo
T
D000230:Adenocarcinoma / Q000201:enzymology; D045744:Cell Line, Tumor; D002474:Cell-Free System; D015179:Colorectal Neoplasms / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; D006880:Hydroxy Acids; D016271:Proto-Oncogene Proteins c-myc; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D011493:Protein Kinase C; D019098:Telomerase