Pizzimenti Stefania, Briatore Federica, Laurora Stefano, Toaldo Cristina, Maggio Maddalena, De Grandi Michela, Meaglia Laura, Menegatti Elisa, Giglioni Barbara, Dianzani Mario U, Barrera Giuseppina
Section of General Pathology, Department of Experimental Medicine and Oncology, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
Free Radic Biol Med. 2006 May 1;40(9):1578-91. doi: 10.1016/j.freeradbiomed.2005.12.024. Epub 2006 Jan 19.
4-Hydroxynonenal (HNE), produced during oxidative stress, has an antiproliferative/differentiative effect in several tumor cells. Recently, it has been observed that oxidative stress accelerates telomere loss. The length of telomeres depends on the telomerase activity, and the catalytic subunit of telomerase (hTERT) is strongly up-regulated in most human cancers and inhibited by differentiating agents. In this paper the inhibitory effect of HNE on telomerase activity and hTERT expression in three human leukemic cell lines (HL-60, U937, ML-1) is reported. To investigate the molecular mechanism involved in hTERT down-regulation by HNE, the expression of several transcription factors was also studied: in all these cell lines, c-Myc was inhibited, Mad-1 was up-regulated, and Sp-1 was not affected. Moreover, in p53 wild-type ML-1 cells, HNE up-regulated p53 expression. In HL-60 cells, DNA binding activity of c-Myc and Mad-1 to the E-box sequence of the hTERT promoter was inhibited and up-regulated, respectively. In summary, HNE inhibits telomerase activity via decreased hTERT promoter activity, by modulating c-Myc/Mad-1 transcription factor expression.
4-羟基壬烯醛（HNE）在氧化应激过程中产生，对多种肿瘤细胞具有抗增殖/分化作用。最近，人们观察到氧化应激会加速端粒丢失。端粒的长度取决于端粒酶活性，端粒酶的催化亚基（hTERT）在大多数人类癌症中强烈上调，并受到分化剂的抑制。本文报道了HNE对三种人类白血病细胞系（HL-60、U937、ML-1）中端粒酶活性和hTERT表达的抑制作用。为了研究HNE下调hTERT的分子机制，还研究了几种转录因子的表达：在所有这些细胞系中，c-Myc受到抑制，Mad-1上调，而Sp-1不受影响。此外，在p53野生型ML-1细胞中，HNE上调了p53的表达。在HL-60细胞中，c-Myc和Mad-1与hTERT启动子E-box序列的DNA结合活性分别受到抑制和上调。总之，HNE通过调节c-Myc/Mad-1转录因子表达，降低hTERT启动子活性，从而抑制端粒酶活性。
