Induction of Apoptosis by Lovastatin through Activation of Caspase-3 and DNase II in Leukaemia HL-60 Cells

Wang, Ing-Kae; Lin‐Shiau, Shoei‐Yn; Lin, Jen‐Kun

doi:10.1034/j.1600-0773.2000.d01-16.x

Cited by 55 publications

(13 citation statements)

References 12 publications

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“…IRF-4 transcriptional downreglation of such genes would lead to an overall decrease in DNA repair and a subsequent increase in cellular mutations seen in HTLV-1 infected T cells, thus contributing to cellular transformation (Hanahan and Weinberg, 2000;Lengauer et al, 1998;Tsukasaki et al, 2000;Yoshida, 2001) (Figure 7). IRF-4 also downregulates several pro-apoptotic genes such as NIP3, RhoB, ALG-2 calcium binding protein, GADD153 and DNAse II in HTLV-1 infected, ATL cells (Table 1) (Bruick, 2000;Lacana et al, 1997;Liu et al, 2001a,b;Lo et al, 1999;Maytin et al, 2001;Wang et al, 2000). IRF-4 has a potential effect on immune recognition of HTLV-1 infected cells as well as on ATL spread and migration to peripheral tissues by modulating LFA-1, RhoA, Grb2, HSC70, RhoB, U-PAR and ezrin expression (Table 1) IRF-4 binds to sites within the cyclin B1 promoter and mediates repression.…”

Section: Discussionmentioning

confidence: 99%

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

et al. 2002

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The human T cell leukemia/lymphotropic virus-1 (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4+ T lymphocytes. Interferon regulatory factor-4 (IRF-4) was shown previously to be constitutively expressed in T cells infected with HTLV-1. In this study, we investigated the role of IRF-4 gene regulation in the context of HTLV-1 infection using gene array technology and IRF-4 expressing T cells. Many potential IRF-4 regulated genes were identified, the vast majority of which were repressed by IRF-4 expression. Cyclin B1, a G2-M checkpoint protein identified as an IRF-4 repressed gene in the array, was further characterized in the context of HTLV-1 infection. All HTLV-1 infected cell lines and ATL patient lymphocytes demonstrated a dramatic decrease in cyclin B1 levels; subsequent analysis of the cyclin B1 promoter identified two sites important in IRF-4 binding and repression of cyclin B1 expression. Furthermore, IRF-4-mediated repression of cyclin B1 led to a significant decrease in CDC2 kinase activity in HTLV-1 infected T cells. IRF-4 expression in HTLV-1 infected T cells also downregulated other genes implicated in the mitotic checkpoint as well as genes involved in actin cytoskeletal rearrangement, DNA repair, apoptosis, metastasis and immune recognition. Several of the identified genes are dysregulated in ATL and may provide important mechanistic information concerning pathways critical to the emergence of ATL.

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Section: Discussionmentioning

confidence: 99%

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

et al. 2002

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“…Subcellular Fractionation-Mitochondrial and cytosolic (S100) fractions were prepared using differential centrifugation (33,(41)(42)(43). Briefly, Jurkat T cells were treated with 5GG or vehicle (Me 2 SO) for the indicated times.…”

Section: Methodsmentioning

confidence: 99%

Induction of G1 Arrest and Apoptosis in Human Jurkat T Cells by Pentagalloylglucose through Inhibiting Proteasome Activity and Elevating p27Kip1, p21Cip1/WAF1, and Bax Proteins

Chen

Lin

2004

Journal of Biological Chemistry

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Pentagalloylglucose, which is found in many medicinal plants, can arrest the cell cycle at G 1 phase through down-regulation of cyclin-dependent kinases 2 and 4 and up-regulation of the cyclin-dependent kinase inhibitors p27 Kip1 and p21 Cip1/WAF1 in human breast cancer cells. Pentagalloylglucose also induces apoptosis in human leukemic cells. However, the mechanisms by which pentagalloylglucose induces these effects is unclear. We now show that pentagalloylglucose inhibits the activities of purified 20 and 26 S proteasomes in vitro, the 26 S proteasome in Jurkat T cell lysates, and chymotrypsinlike activity of the 26 S proteasome in intact Jurkat T cells. The turnover of p27 Kip1 and p21 Cip1/WAF1 , which is necessary for cell cycle progression mediated by proteasome degradation, was disrupted by treatment of human Jurkat T cells with pentagalloylglucose. This was shown by cycloheximide treatment and in vivo pulsechase labeling experiments, and this effect correlated with the arrest of proliferation of Jurkat T cells at G 1 . Inhibition of the proteasome by pentagalloylglucose and by the proteasome inhibitor MG132 caused accumulation of ubiquitin-tagged proteins in Jurkat T cells. The addition of pentagalloylglucose to Jurkat T cells enhanced the stability of the proteasome substrate Bax and increased cytochrome c release and apoptosis. Our findings suggest a mechanism for the effect of pentagalloylglucose on the cell cycle in human leukemic cells: that pentagalloylglucose down-regulates proteasomemediated pathways because it is a proteasome inhibitor.In eukaryotic cells, there are two distinct proteolytic mechanisms essential for regulating levels of cellular proteins. One is lysosomal mediated degradation, which is involved in the breakdown of intracellular proteins under conditions of cellular stress, membrane-associated proteins, and proteins that have entered the cell by endocytosis. The ubiquitin-proteasome pathway is the other mechanism responsible for the turnover of intracellular proteins. This second system works by marking specific substrates with ubiquitins and degrading the marked proteins by the 26 S proteasome in an ATP-dependent manner.

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“…Statins may impair the metastatic potential of tumor cells, too. Statins reduced endothelial leukocyte adhesion molecule E-selectin (Nubel et al 2004) and matrix metalloproteinase-9 expression (Wang et al 2000). Fluvastatin and lovastatin inhibited liver tumorigenesis and liver metastasis in pancreatic cancer cells (Kusama et al 2002) and atorvastatin decreased melanoma cell metastasis (Collisson et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

et al. 2011

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Epidemiological studies indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, play a role in inhibition of several human neoplasia including breast cancer. In this study, chemopreventive effects of atorvastatin in N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. Atorvastatin was administered in the diet at two concentrations: 10 mg/kg (ATOR 10) and 100 mg/kg (ATOR 100). Atorvastatin treatment began 8 days prior to carcinogen administration and subsequently continued for 15 weeks till the end of the experiment. Atorvastatin at a higher dose suppressed tumor frequency by 80.5% (P = 0.0008) and tumor incidence by 49.5% (P = 0.015), and extended latency period by 14 days (P = 0.076) when compared to the control group. Atorvastatin at a lower dose did not significantly alter tumor parameters in comparison with the control group. In the specimens of mammary tumors, atorvastatin (in the ATOR 100 group) significantly decreased mRNA expression of Bcl-2 gene but non-significantly increased Bax mRNA expression compared to control group. Atorvastatin administration did not alter serum concentration of triacylglycerols, total cholesterol, and LDL cholesterol in comparison with controls. This study is the first report on tumor suppressive effect of atorvastatin in rat mammary carcinogenesis.

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Induction of Apoptosis by Lovastatin through Activation of Caspase-3 and DNase II in Leukaemia HL-60 Cells

Cited by 55 publications

References 12 publications

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

Induction of G1 Arrest and Apoptosis in Human Jurkat T Cells by Pentagalloylglucose through Inhibiting Proteasome Activity and Elevating p27Kip1, p21Cip1/WAF1, and Bax Proteins

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

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