Biomedical subjects

Wei-Jun Liu

Publications and source records attributed to Wei-Jun Liu.

4 recordsLinked to original sources

PubMed2004

Telomerase inhibition is a specific early event in salvicine-treated human lung adenocarcinoma A549 cells.

The telomere and telomerase have been suggested as targets for anticancer drug discovery. However, the mechanisms by which conventional anticancer drugs affect these targets are currently unclear. The novel topoisomerase II inhibitor, salvicine, suppresses telomerase activity in leukemia HL-60 cells. To further determine whether this activity of salvicine is specific to the hematological tumor and distinct from those of other conventional anticancer agents, we studied its effects on telomere and telomerase in a solid lung carcinoma cell line, A549. Differences in telomerase inhibition and telomere erosion were observed between salvcine and other anticancer agents. All anticancer agents (except adriamycin) induced shortening of the telomere, which was identified independent of replication, but only salvicine inhibited telomerase activity in A549 cells under conditions of high concentration and short-term exposure. At the low concentration and long-term exposure mode, all the tested anticancer agents shortened the telomere and inhibited telomerase activity in the same cell line. Notably, salvicine inhibited telomerase activity more severely than the other agents examined. Moreover, the compound inhibited telomerase activity in A549 cells indirectly in a concentration- and time-dependent manner. Salvicine did not affect the expression of hTERT, hTP1, and hTR mRNA in A549 cells following 4 h of exposure. Okadaic acid protected telomerase from inhibition by salvicine. These results indicate specificity of salvicine and diversity of anticancer agents in the mechanism of interference with telomerase and the telomere system. Our data should be helpful for designing the study in the development of agents acting on telomere and/or telomerase.

Adenocarcinoma↗

PubMed2004

Alternative splicing of human telomerase reverse transcriptase may not be involved in telomerase regulation during all-trans-retinoic acid-induced HL-60 cell differentiation.

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 down-regulation 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. Expression of full length variant hTERT alpha+ beta+ mRNA decreased in a dose- and time-dependent manner. The drop of hTERT beta- mRNA was time-dependent. hTERT alpha- and hTERT alpha- beta- mRNA were reduced dramatically after ATRA treatment. In the dose-effect study, hTERT alpha+ beta+ and hTERT beta- maintained a relatively stable ratio when telomerase activity decreased largely from treatment with 1 to 5 microM 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.

Alternative Splicing↗

PubMed2003

[Protein phosphatase 2A: its structure, function and activity regulation].

Protein phosphatase 2A (PP2A) is a major kind of serine/threonine protein phosphatase in eukaryotic cells. PP2A has many subunits and isozymes encoded by different genes to form many different PP2A holoenzymes. PP2A plays important roles in regulation of cell cycle, signal transduction, cell differentiation, and transformation. Its activity is related to several diseases, including neurodegenerative diseases and cancer. The regulation of PP2A activity is accomplished by its subunits' expression, cellular localization, phosphorylation and methylation. The second messenger, ceramide, also plays an important role in the regulation of PP2A activity, as well as a plenty of low molecular mass inhibitors of PP2A and other protein phosphatases.

Animals↗

PubMed2002

Down-regulation of telomerase activity via protein phosphatase 2A activation in salvicine-induced human leukemia HL-60 cell apoptosis.

Salvicine is a novel topoisomerase II inhibitor possessing significant antitumor activity, both in vitro and in vivo. The antitumor effect of salvicine is associated with its ability to induce tumor cell apoptosis. Telomerase plays an important role in the apoptotic pathway. However, little is known about the mechanisms of telomerase regulation during apoptosis induced by anticancer drugs. This study investigated the regulation of telomerase activity in salvicine-induced human leukemia HL-60 cell apoptosis. Salvicine treatment resulted in HL-60 cell apoptosis and down-regulation of telomerase activity in a time- and concentration-dependent manner. Repression of telomerase activity preceded a decrease in expression of the telomerase catalytic subunit (hTERT) and telomerase-associated protein (TP1) at the mRNA level, suggesting that the salvicine-induced decrease in telomerase activity may be additionally regulated by mechanisms other than telomerase subunit transcription. We observed that okadaic acid (OA), a protein phosphatase inhibitor, prevented the induction of apoptosis and the down-regulation of telomerase activity by salvicine. The significant increase in protein phosphatase 2A (PP2A) activity induced by salvicine treatment was blocked completely by OA. Moreover, although salvicine induced HL-60 cell apoptosis in a caspase-3-dependent manner, a specific caspase-3 inhibitor, Z-DEVD-FMK, did not prevent a decrease in telomerase activity or an increase in PP2A activity in apoptotic HL-60 cells, ruling out a role for caspase-3 in PP2A activation by salvicine. The results collectively suggest that the salvicine-induced decline in telomerase activity is not a consequence of HL-60 cell apoptosis and that it may be caused principally by the dephosphorylation of telomerase components mediated by PP2A activation.

Apoptosis↗