4-Hydroxynonenal inhibits telomerase activity and hTERT expression in human leukemic cell lines

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Oxidative stress produces 4-hydroxynonenal (HNE), which has antiproliferative effects on tumor cells.
• Oxidative stress accelerates telomere loss, impacting cell aging and cancer progression.
• Telomere length is regulated by telomerase activity, with human telomerase reverse transcriptase (hTERT) often upregulated in cancers.

Purpose of the Study:

• To investigate the inhibitory effect of HNE on telomerase activity and hTERT expression in human leukemia cell lines.
• To elucidate the molecular mechanisms underlying HNE-induced hTERT downregulation.
• To examine the role of transcription factors c-Myc, Mad-1, Sp-1, and p53 in mediating HNE's effects.

Main Methods:

• Treatment of human leukemia cell lines (HL-60, U937, ML-1) with HNE.
• Analysis of telomerase activity and hTERT expression.
• Study of transcription factor expression (c-Myc, Mad-1, Sp-1, p53) and DNA binding activity to the hTERT promoter.

Main Results:

• HNE inhibited telomerase activity and hTERT expression in all tested leukemia cell lines.
• HNE modulated transcription factor expression: c-Myc was inhibited, Mad-1 was upregulated, and Sp-1 was unaffected.
• In p53 wild-type ML-1 cells, HNE upregulated p53 expression. In HL-60 cells, HNE altered c-Myc and Mad-1 DNA binding to the hTERT promoter.

Conclusions:

• HNE inhibits telomerase activity in human leukemia cells by decreasing hTERT promoter activity.
• The mechanism involves the modulation of c-Myc and Mad-1 transcription factor expression and activity.
• HNE represents a potential therapeutic agent targeting telomerase in leukemia.