Abstract
Telomere and Telomerase have recently been explored as anti-aging and anti-cancer drug targets with only limited success. Previously we showed that the Chinese herbal medicine Tianshengyuan-1 (TSY-1), an agent used to treat bone marrow deficiency, has a profound effect on stimulating Telomerase activity in hematopoietic cells. Here, the mechanism of TSY-1 on cellular Telomerase activity was further investigated using HL60, a promyelocytic leukemia cell line, normal peripheral blood mononuclear cells, and CD34+ hematopoietic stem cells derived from umbilical cord blood. TSY-1 increases Telomerase activity in normal peripheral blood mononuclear cells and CD34+ hematopoietic stem cells with innately low Telomerase activity but decreases Telomerase activity in HL60 cells with high intrinsic Telomerase activity, both in a dose-response manner. Gene profiling analysis identified Telomerase reverse transcriptase (TERT) as the potential target gene associated with the TSY-1 effect, which was verified by both RT-PCR and western blot analysis. The β-galactosidase reporter staining assay showed that the effect of TSY-1 on Telomerase activity correlates with cell senescence. TSY-1 induced hypomethylation within TERT core promoter in HL60 cells but induced hypermethylation within TERT core promoter in normal peripheral blood mononuclear cells and CD34+ hematopoietic stem cells. TSY-1 appears to affect the Telomerase activity in different cell lines differently and the effect is associated with TERT expression, possibly via the methylation of TERT promoter.
Highlights
Over the past two decades, there has been intense interest in the study of the regulation of Telomerase, which is an RNA-dependent DNA polymerase
Our current study demonstrated that TSY1 has profound effects on maintaining the homeostasis of Telomerase activity: it inhibits the Telomerase activity in cancerous HL60 cells, which has high intrinsic Telomerase activity, whereas it increases Telomerase activity in normal peripheral blood mononuclear cells (PBMCs) and CD34+ hematopoietic stem cells (HSCs) derived from umbilical cord blood
TSY-1 treatment increased Telomerase activity in PBMCs and HSCs compared to the untreated control
Summary
Over the past two decades, there has been intense interest in the study of the regulation of Telomerase, which is an RNA-dependent DNA polymerase. Earlier studies demonstrated that over 80% of all cancer types showed increased Telomerase activity and increased Telomere length in cancer cells over their normal cell counterparts [1]. This together with activating oncogenes / deactivating tumor suppressor genes result in the dysregulation of tumor cell growth and proliferation [2, 3]. Www.impactjournals.com/oncotarget these efforts have resulted in only limited success This is partly due to the fact that cellular Telomerase homeostasis, including Telomerase activity and Telomere length, is regulated by a complex network of genes that have interconnected signals
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