Alternative Splicing of Human Telomerase Reverse Transcriptase May Not Be Involved in Telomerase Regulation During all-trans-Retinoic Acid-Induced HL-60 Cell Differentiation

Abstract

Abstract. Alternative splicing of the human telomerase reverse transcriptase subunit (hTERT) suppresses telomerase activity during the development of human fetal kidney cells into mature cells. Tumor cell differentiation is the process of turning abnormal tumor cells into 'normal' cells accompanied by down-regulation of telomerase activity. However, the precise mechanism of the regulation of telomerase activity in differentiated cells is not fully understood. In this study, we observed the role of alternative splicing of hTERT in the regulation of telomerase activity in all-trans-retinoic acid (ATRA)-induced, differentiated HL-60 cells. ATRA-induced downregulation of telomerase activity in differentiated HL-60 cells was associated with a decrease in hTERT and an increase in human telomerase-associated protein-1 (hTP1) transcription. and hTERT b -maintained a relatively stable ratio when telomerase activity decreased largely from treatment with 1 to 5 m M ATRA. Although the splicing pattern of hTERT mRNA was altered in time-effect research, the change was not related to the ATRA-treated decline of telomerase activity. The expression of alternative splicing variants of hTERT also decreased at the protein level. All these results suggested that alternative splicing of hTERT mRNA may not contribute to the suppression of telomerase activity during ATRA-induced HL-60 leukemia cell differentiation.

Microenvironmental Regulation of Telomerase Isoforms in Human Embryonic Stem Cells

“…These hTERT deletion variants are detected in a number of cancers and tumor cell lines and additionally during development displaying tissue-specific and gestationalage-dependent expression patterns that reduce telomerase activity levels and may influence variations in telomere lengths [35][36][37]. However, additional efforts have revealed that no correlation exists between the levels of TERT splice variants and the decrease in telomerase activity observed during cellular differentiation [38,39]. Therefore, it is necessary to consider other function(s) for alternatively spliced variants of TERT beyond modulating telomerase activity, as these roles would reveal novel mechanisms of controlling stem cell function [40].…”

Anti-Metastatic Study of Liposome-Encapsulated AlltransRetinoic Acid (ATRA) in B16F10 Melanoma Cells-Implanted C57BL/6 Mice

“…A single dose of liposomeencapsulated ATRA can directly induce molecular remissions in APL patients, wherein ATRA is being used as the first drug of choice for treatment of APL. However, ATRA is used as a chemotherapeutic drug or supplementary drug in pre-clinical studies as well as used clinically to treat other cancers/solid tumors such as lung cancer, breast cancer, and liver cancer (3)(4)(5), but their remission rate is less. One possible reason may be that it may not have reached the target site in sufficient concentration, which may have led to complete remission of these solid cancers such as APL.…”

“…Retinoic acid promotes the production of interleukin (IL) and interferon (IFN) for preventing viruses and other external factors from entering the tissue (14). Retinoic acid has been shown to have antitumor activity in several experimental mice models (3)(4)(5).…”

Inhibition of metastatic lung cancer in C57BL/6 mice by liposome encapsulated all trans retinoic acid (ATRA)

“…ATRA and its other active derivatives are potent modulators of cell growth, differentiation, and apoptosis in a variety of cell types [6,7]. They can also be used as chemotherapeutic and chemopreventive agents in a variety of malignancies, such as leukemias, uterine leiomyomas, as well as colon, gastric, solid tumor and breast cancers [8][9][10]. Retinoic acid (RA) has also been suggested to be efficacious in treating lung cancer [11,12].…”