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Biomedical subjects

X K Li

Publications and source records attributed to X K Li.

At least 73 records · Page 4Linked to original sources
PubMed1997

An immunosuppressive agent, FTY720, increases intracellular concentration of calcium ion and induces apoptosis in HL-60.

We previously reported that FTY720 is an efficient inducer of apoptosis in lymphocytes and cultured cell lines. In the present study, HL-60 human promyerocytoma cells also induced apoptosis through in vitro treatment with the drug, demonstrating extensive DNA fragmentation 6 hr after incubation. The major target of FTY720 was the common signalling pathway of apoptosis, since a rapid (< 1 min) increase in the intracellular Ca2+ concentration ([Ca2+]i) was found in the cells treated with the drug. Calcium chelation in the culture medium with EGTA did not affect the [Ca2+]i mobilization. A phospholipase C inhibitor, U73122, inhibited the increase in [Ca2+]i as well as the fragmentation of the nuclear DNA, whereas U73343, a non-effective analogue of U73122, had little effect. These results suggest that FTY720-induced apoptosis is mediated through an activation of phospholipase C and the subsequent release of Ca2+ from intracellular calcium pools. In addition, the treatment of HL-60 with pertussis toxin (PTX) did not inhibit Ca2+ mobilization or apoptosis, suggesting that the activation of phospholipase C is independent of PTX-sensitive G-proteins.

Apoptosis↗
PubMed1996

Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720.

A novel immunosuppressant, FTY720, induces a rapid and marked decrease of peripheral lymphocytes, and prolong allograft survival in rats. Its mechanism of action is mediated by apoptotic cell death. In this study, we determined the time-related changes in the numbers of total lymphocytes, and the ratios of lymphocyte subpopulations in peripheral blood and lymphomyeloid organs in rats after the single oral administration of FTY720 (10 mg/kg), comparing with the effects of cyclophosphamide (80 mg/kg, ip). Total number of peripheral lymphocytes decreased significantly 3 h after the administration of the drug, while that of polymorphonuclear cells increased. T-cells were markedly decreased in number and reached a minimum of 2.3% of the control 3 days after the treatment, while B-cells reached 19.7%. T-cells decreased in spleen and liver but there was no notable change in thymus, lymph nodes, and bone marrow. The susceptibility of the cells against the drug was variant based on the type and the source of cells in vitro. Polymorphonuclear cells were the most resistant and lymph node cells the most sensitive to FTY720 after 3 h incubation with different concentration of the drug (1, 10,100 mumol/l). When incubated with 10 mumol/l of FTY720, B-cells were significantly higher in viability than the whole T- or CD4-cells. These results demonstrated that FTY720 induces cell death selectively in mature T-lymphocytes, especially CD4-lymphocytes, in peripheral blood without the depression of bone marrow.

Animals↗
PubMed1996

Elevation of intracellular cyclic adenosine monophosphate inhibits the epidermal growth factor signal transduction pathway and cellular growth in pancreatic adenocarcinoma cell lines.

BACKGROUND: The epidermal growth factor (EGF) signal transduction pathway, frequently activated in pancreatic cancer, is an important regulator of cellular growth and transformation. This study examined whether activation of the cyclic adenosine monophosphate protein kinase A pathway may inhibit the EGF signal transduction pathway in pancreatic cancer cell lines. METHODS: Human pancreatic cancer lines BxPC-3 and AsPC-1 were stimulated with EGF, forskolin, or both. Forskolin is a compound that increases cyclic adenosine monophosphate levels. Assays of cell lines were then obtained for cellular growth (MTT assay), anchorage-independent growth (soft agar), and EGF-induced mitogen-activated protein kinase activation as measured by an in-gel kinase assay. RESULTS: Treatment with forskolin resulted in inhibition of EGF-induced activation of mitogen-activated protein kinase activity (BxPC-3 78% inhibition and AsPC-1 70% inhibition, p < 0.005), diminished cellular proliferation (BxPC-3 92% inhibition and AsPC-1 86% inhibition, p < 0.001), and formation of colonies in soft agar (BxPC-3 98% inhibition and AsPC-1 76% inhibition, p < 0.001). Forskolin did not inhibit EGF receptor autophosphorylation or tyrosine kinase signaling in response to EGF. CONCLUSIONS: Forskolin-induced inhibition of mitogen-activated protein kinase is associated with diminished pancreatic cancer cell proliferation in vitro. Use of strategies to increase cyclic adenosine monophosphate levels may have therapeutic application in pancreatic cancer.

Adenocarcinoma↗
PubMed1996

A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes.

FTY720 is a unique immunosuppressive drug produced by modification of a metabolite from Isaria sinclairii. In vitro treatment of human mononuclear cells with FTY720 resulted in a dose-dependent reduction of cell viability. These treated cells demonstrated characteristic DNA ladder formation on agarose gel electrophoresis. Jurkat cells transfected with human bcl-2 gene were resistant to FTY720; their neo type was susceptible to the drug. A rapid acceleration of cell death in human mononuclear cells was seen as early as 2 hr after incubation with FTY720. The intracellular Bax protein increased remarkably 1 hr after the culture; it markedly decreased in the surviving cells at 2 and 3 hr. Coincidental to the Bax decrease. Bcl-2 progressively decreased beginning 2 hr after the culture. Thus, the ratio of Bcl-2 to Bax was decreased by the enhanced expression of Bax immediately after FTY720-treatment, resulting in rapid cell death acceleration. The surviving cells (FTY720-resistant cells) at 2 and 3 hr after culture showed a similar ratio of Bcl-2 to Bax as was observed in the control cells. These results suggest that FTY720 displays bcl-2-associated apoptotic cell death in human mononuclear cells.

Apoptosis↗
PubMed1995

LckBP1, a proline-rich protein expressed in haematopoietic lineage cells, directly associates with the SH3 domain of protein tyrosine kinase p56lck.

The Lck tyrosine kinase molecule plays an essential role in T cell activation and T cell development. Using the expression cloning technique, we have isolated a gene that encodes a molecule, LckBP1, able to associate with murine Lck. Analysis of full-length LckBP1 cDNA indicates at least four potentially important segments: a four tandem 37 amino acid repeat motif with a potential helix-turn-helix DNA binding motif; a proline-rich region; a proline-glutamate repeat; and an SH3 domain. These four regions are very similar to the human haematopoietic-specific protein 1 (HS1). Deletion mutant analysis of LckBP1 revealed two proline-rich regions that permit association with Lck SH3. One region contains prolines conserved among HS1 and cortactin, and the other region contains a potential MAP kinase recognition site. In vivo association between Lck and LckBP1 was confirmed by immunoprecipitation of lysates from a pre-T cell line and adult thymocytes using antibodies specific for Lck and LckBP1. LckBP1 is tyrosine phosphorylated after T-cell receptor stimulation. The SH3 domain and the potential helix-turn-helix motif in LckBP1 suggest that this molecule may associate with various molecules and function as a DNA binding molecule. The data also suggest that LckBP1 mediates intracellular signalling through Lck in T cells.

3T3 Cells↗