Thiazolidinedione Induces Apoptosis and Monocytic Differentiation in the Promyelocytic Leukemia Cell Line HL60

Hirase, Nobuhisa; Yanase, Toshihiko; Mu, Yi Ming; Muta, Koichiro; Umemura, Tomonari; Takayanagi, Ryoichi; Nawata, Hajime

doi:10.1159/000055271

Cited by 56 publications

(29 citation statements)

References 22 publications

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“…Apoptosis induction by PPARg ligands has been demonstrated in a variety of cell lines (Elstner et al, 1998(Elstner et al, , 2002Mueller et al, 1998;Kitamura et al, 1999;Takahashi et al, 1999;Chang and Szabo, 2000;Padilla et al, 2000;Tsubouchi et al, 2000;Eibl et al, 2001, Kawa et al, 2002. In the HL60 leukemia cell line, TG suppressed cell proliferation and induced apoptosis at concentrations of 25-50 mM (Hirase et al, 1999), which were similar to what we used in our experiment. The authors of the above study suggested that TG-induced apoptosis and differentiation might be mutually associated.…”

Section: Discussionsupporting

confidence: 83%

“…In hematopoietic cells, peripheral mononuclear cells and several human leukemia cell lines have been reported to express PPARg (Greene et al, 1995). TZD initiates monocytic differentiation in the promyelocytic leukemia cell line HL60 and induces apoptosis at a high concentration (Hirase et al, 1999). PPARg expression and its significance in apoptosis have also recently been evaluated in human B lymphocytes (Padilla et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Expression of NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis

2003

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We have investigated the effects of acute promyelocytic leukemia (APL) fusion gene NPM-RARa on the function of PPARc using the monoblastic cell line U937. U937 cells were transduced using a retrovirus carrying NPMRARa. While treatment with the synthetic PPARc ligand troglitazone (TG) had no effect on the viability of U937 cells, TG treatment of U937/NPM-RARa cells resulted in a dramatic decrease in cell viability, dependent upon both the concentration of TG and the level of expression of NPM-RARa. Analysis of the cell cycle profile and flow cytometry with annexin V confirmed that these effects of TG were due to induction of apoptosis. Induction of apoptosis was accompanied by caspase-8 and caspase-9 activation, and could be blocked by treatment with the caspase inhibitor Z-VAD-FMK. Cotreatment of U937/ NPM-RARa cells with all-trans retinoic acid (atRA) abrogated the induction of apoptosis by TG. Induction of apoptosis was seen also in the PML-RARa-expressing APL cell line NB4, and in several other atRA-sensitive leukemia cell lines, demonstrating that this effect is limited neither to the monocyte lineage nor to the rare NPM-RARa fusion variant. RXRa/NPM-RARa heterodimers were found to interact directly with a PPARcresponsive element in vitro. We conclude that in the presence of X-RARa, TG induces cell death due to apoptosis via the caspase pathway. These observations suggest the investigation of PPARc ligands as therapeutic agents in acute leukemia.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Expression of NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis

2003

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“…TRO was shown to causes apoptosis of many different cell lines including: endothelial cells, monocyte-derived macrophages (Chinetti et al, 1998), six colon cell lines (Kitamura et al, 1999), HL60 promyelocytic leukemia cells (Hirase et al, 1999), and vascular smooth muscle cells (Okura et al, 2000). TRO was recently shown to induce apoptosis in human liver cancer cells (Toyoda et al, 2001(Toyoda et al, , 2002.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

Bae

Song²

2003

Molecular Pharmacology

125

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The peroxisome proliferator-activated receptor agonist troglitazone (TRO) was used for treatment of non-insulin-dependent diabetes until its removal from the market because of its severe hepatotoxicity. However, the mechanism for its hepatotoxicity is still poorly understood. In this study, we investigated whether TRO caused cell death by altering signaling pathways associated with cell damage and survival in human hepatoma cells. Our data reveal that TRO caused time-and concentrationdependent apoptosis of HepG2 and Chang liver human hepatoma cells, as evidenced by DNA fragmentation and staining with Hoechst 33342. In contrast, 50 or 100 M rosiglitazone, a structural analog of TRO, did not cause apoptosis in these hepatoma cells. TRO activated both c-Jun N-terminal protein kinase (JNK) and p38 kinase about 5-fold between 0.5 and 8 h before they returned to control levels at 16 h in HepG2 cells. In contrast, TRO failed to activate the extracellular signal-regulated kinase. Furthermore, TRO increased the levels of proapoptotic proteins, Bad, Bax, release of cytochrome c, and cleavage of Bid in a time-dependent manner. The antiapoptotic Bcl-2 protein level decreased in hepatoma cells treated with TRO. Pretreatment of hepatoma cells with a selective JNK inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), significantly reduced the rate of TRO-induced cell death, whereas 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), an inhibitor of p38 kinase, had little effect on apoptosis. Pretreatment with SP600125 also prevented JNK activation and c-Jun phosphorylation. In addition, rosiglitazone, which is not as toxic to hepatoma cells as TRO, did not stimulate JNK activity. Transfection of cDNA for the dominant-negative mutant JNK-KR (Lys3 Arg) or SEK1-KR (Lys3 Arg), an immediate upstream kinase of JNK, significantly reduced TRO-induced JNK activation and cell death rate. Furthermore, SP600125 pretreatment effectively prevented the TRO-mediated changes in Bad, Bax, Bid cleavage, and cytochrome c release. These data strongly suggest that hepatotoxic TRO causes apoptosis by activating the JNK-dependent cell death pathway accompanied by increased Bid cleavage and elevation of proapoptotic proteins.

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“…These lipidsensitive receptors can be activated in a variable isotypespecific manner by natural fatty acids, leukotrienes, prostaglandins, and some synthetic agonists, including antidiabetic drugs, such as rosiglitazone, ciglitazone, and pioglitazone. These drugs are also effective in regulating cell activation, differentiation, proliferation, and/or apoptosis (3,4).…”

Section: Introductionmentioning

confidence: 99%

Rosiglitazone suppresses human lung carcinoma cell growth through PPARγ-dependent and PPARγ-independent signal pathways

Han

Roman

2006

Molecular Cancer Therapeutics

155

135

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Peroxisome proliferator-activated receptors ; (PPAR;) exert diverse effects on cancer cells. Recent studies showed that rosiglitazone, a synthetic ligand for PPAR;, inhibits cell growth. However, the exact mechanisms underlying this effect are still being explored, and the relevance of these findings to lung cancer remains unclear. Here, we report that rosiglitazone reduced the phosphorylation of Akt and increased phosphatase and tensin homologue (PTEN) protein expression in nonsmall cell lung carcinoma (NSCLC) cells (H1792 and H1838), and this was associated with inhibition of NSCLC cell proliferation. These effects were blocked or diminished by GW9662, a specific PPAR; antagonist. However, transfection with a CMX-PPAR;2 overexpression vector restored the effects of rosiglitazone on Akt, PTEN, and cell growth in the presence of GW9662. In addition, rosiglitazone increased the phosphorylation of AMP-activated protein kinase A (AMPKA), a downstream kinase target for LKB1, whereas it decreased phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream target of mammalian target of rapamycin (mTOR). Of note, GW9662 did not affect the phosphorylation of AMPKA and p70S6K protein. The inhibitory effect of rosiglitazone on NSCLC cell growth was enhanced by the mTOR inhibitor rapamycin; however, it was blocked, in part, by the AMPKA small interfering RNA. Taken together, these findings show that rosiglitazone, via up-regulation of the PTEN/AMPK and down-regulation of the Akt/mTOR/p70S6K signal cascades, inhibits NSCLC cell proliferation through PPAR;-dependent and PPAR;-independent signals. [Mol Cancer Ther 2006;5(2):430 -7]

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Thiazolidinedione Induces Apoptosis and Monocytic Differentiation in the Promyelocytic Leukemia Cell Line HL60

Cited by 56 publications

References 22 publications

Expression of NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis

Expression of NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

Rosiglitazone suppresses human lung carcinoma cell growth through PPARγ-dependent and PPARγ-independent signal pathways

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