Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade

Jun, Do Youn; Kim, Jun; Park, Hae S.; Han, Cho Rong; Fang, Zhe; Woo, Mi Hee; Rhee, In Koo; Kim, Young H.

doi:10.1093/carcin/bgm028

Cited by 76 publications

(83 citation statements)

References 51 publications

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“…Again, there was a remarkable enhancement in the level of G2/M cells, upon the blocking of 17α-E2-mediated apoptosis by z-VAD-fmk, confirming that the apoptosis was mainly induced in the G2/M cells via the caspase activation. Although the endoplasmic reticulum stress-mediated activation of caspase-8 was previously upstream of mitochondrial cytochrome c release in the chemical agent-induced apoptosis of tumor cells (Jimbo et al, 2003;Jun et al, 2007), it was not the case for the 17a-E2-mediated activation of caspase-8. This is because the caspase-9 activation was induced by 17α-E2, regardless of the individual or simultaneous presence of caspase-8 inhibitor (z-IETD-fmk), m-calpain inhibitor (E64d), and JNK inhibitor (SP600125), and both the caspase-3 activation and PARP cleavage were reduced, but not completely, by the presence of z-IETDfmk.…”

Section: Discussionmentioning

confidence: 97%

“…To confirm that the mitochondrial cytochrome c release and subsequent activation of caspase cascade were critical for the 17α-E2-mediated apoptosis, we have employed two experimental approaches; one was to take advantage of the antiapoptotic protein Bcl-2 which can suppress mitochondrial cytochrome c release as well as endoplasmic reticulum stressmediated activation of caspase-8 (Jimbo et al, 2003;Jun et al, 2007), and the other was to use caspase inhibitors, such as z-VAD-fmk, the broad range caspase inhibitor (Slee et al, 1996), and z-IETD-fmk, the caspase-8 inhibitor (Takizawa et al, 1999). 17α-E2-mediated apoptosis was completely abrogated by the overexpression of Bcl-2, whereas the accumulation of G2/M cells was significantly enhanced.…”

Section: Discussionmentioning

confidence: 99%

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17α-Estradiol arrests cell cycle progression at G2/M and induces apoptotic cell death in human acute leukemia Jurkat T cells

Jun

Park

Kim

et al. 2008

Toxicology and Applied Pharmacology

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A pharmacological dose (2.5-10 μM) of 17α-estradiol (17α-E2) exerted a cytotoxic effect on human leukemias Jurkat T and U937 cells, which was not suppressed by the estrogen receptor (ER) antagonist ICI 182,780. Along with cytotoxicity in Jurkat T cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3, and -8, PARP degradation, and DNA fragmentation were induced. The cytotoxicity of 17α-E2 was not blocked by the anti-Fas neutralizing antibody ZB-4. While undergoing apoptosis, there was a remarkable accumulation of G2/M cells with the upregulation of cdc2 kinase activity, which was reflected in the Thr56 phosphorylation of Bcl-2. Dephosphorylation at Tyr15 and phosphorylation at Thr161 of cdc2, and significant increase in the cyclin B1 level were underlying factors for the cdc2 kinase activation. Whereas the 17α-E2-induced apoptosis was completely abrogated by overexpression of Bcl-2 or by pretreatment with the pan-caspase inhibitor z-VAD-fmk, the accumulation of G2/M cells significantly increased. The caspase-8 inhibitor z-IETD-fmk failed to influence 17α-E2-mediated caspase-9 activation, but it markedly reduced caspase-3 activation and PARP degradation with the suppression of apoptosis, indicating the contribution of caspase-8; not as an upstream event of the mitochondrial cytochrome c release, but to caspase-3 activation. In the presence of hydroxyurea, which blocked the cell cycle progression at the G1/S boundary, 17α-E2 failed to induce the G2/M arrest as well as apoptosis. These results demonstrate that the cytotoxicity of 17α-E2 toward Jurkat T cells is attributable to apoptosis mainly induced in G2/M-arrested cells, in an ER-independent manner, via a mitochondriadependent caspase pathway regulated by Bcl-2.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

17α-Estradiol arrests cell cycle progression at G2/M and induces apoptotic cell death in human acute leukemia Jurkat T cells

Jun

Park

Kim

et al. 2008

Toxicology and Applied Pharmacology

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“…Cell lysates were prepared by using a lysis buffer (137 mM NaCl, 15 mM EGTA, 1 mM sodium orthovanadate, 15 mM MgCl2, 0.1% Triton X-100, 25 mM MOPS, 2.5 μg/ml proteinase inhibitor E-64, pH 7.2) as described previously [12]. An equivalent amount of cell lysate (20 μg) was denatured with SDS sample buffer, and subjected to electrophoresis on 4-12% SDS gradient polyacrylamide gel with MOPS buffer.…”

Section: Preparation Of Cell Lysate and Western Blot Analysismentioning

confidence: 99%

“…To assess mitochondrial cytochrome c release in Jurkat T cells following SS-8 treatment, cytosolic protein extracts were obtained as described elsewhere [12]. The cytosolic extracts free of mitochondria were analyzed for cytochrome c by Western blotting.…”

Section: Detection Of Mitochondrial Cytochrome C In Cytosolic Proteinmentioning

confidence: 99%

“…Recently, we have reported that the methylene chloride extract from the leaves of Z. schinifolium possesses antitumor activity against human acute leukemia Jurkat T cells, which results from induction of apoptotic cell death, and chemical compositions of the methylene chloride extract [14]. More recently, we have investigated the apoptogenic mechanism for 7-[(3,7-dimethyl-2,6-octadienyl)-oxy]-coumarin (auraptene) purified from the leaves of Z. schinifolium, and found that auraptene induces apoptotic cell death of Jurkat T cells through the endoplasmic reticulum stress-mediated activation of caspase-8, and the subsequent induction of mitochondria-dependent or mitochondria-independent activation of caspase cascade [12]. Until now, however, there is no report on the cytotoxic effect of the stems of Z. schinifolium, and its cytotoxicity toward human tumor cells.…”

Section: Introductionmentioning

confidence: 99%

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Apoptosis of Human Jurkat T Cells Induced by the Methylene Chloride Extract from the Stems of Zanthoxylum schinifolium is Associated with Intrinsic Mitochondria-Dependent Activation of Caspase Pathway

Jun¹,

Woo²,

Park³

et al. 2008

Journal of Life Science

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Dulxanthone A induces cell cycle arrest and apoptosis via up‐regulation of p53 through mitochondrial pathway in HepG2 cells

Tian

Shen

Moseman

et al. 2007

Intl Journal of Cancer

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Natural products derived from plants provide a rich source for development of new anticancer drugs. Dulxanthone A was found to be an active cytotoxic component in Garcinia cowa by bioactivity-directed isolation. Studies to elucidate the cytotoxic mechanisms of dulxanthone A showed that dulxanthone A consistently induced S phase arrest and apoptosis in the most sensitive cell line HepG2. Furthermore, p53 was dramatically up-regulated, leading to altered expression of downstream proteins upon dulxanthone A treatment. Cell cycle related proteins, such as cyclin A, cyclin B, cyclin E, cdc-2, p21 and p27 were down-regulated. Some apoptosis correlated proteins were also altered following the drug treatment. Bcl-2 family members PUMA was up-regulated while Bcl-2 and Bax were down-regulated. However, the expression ratio of Bax/Bcl-2 was increased. This resulted in the release of cytochrome C from the mitochondria to the cytosol. Concurrently, Apaf-1 was stimulated with p53 by dulxanthone A. In result, cytochrome C, Apaf-1 and procaspase-9 form an apoptosome, which in turn triggered the activation of caspase-9, caspase-3 and downstream caspase substrates. Lamin A/C and PARP were down-regulated or cleaved, respectively. Moreover, cell cycle arrest and apoptosis in HepG2 cells induced by dulxanthone A were markedly inhibited by siRNA knockdown of p53. In summary, dulxanthone A is an active cytotoxic component of G. cowa. It induces cell cycle arrest at lower concentrations and triggers apoptosis at higher concentrations via up-regulation of p53 through the intrinsic mitochondrial pathway in HepG2 cells. Dulxanthone A is therefore likely a promising preventive and/or therapeutic agent against Hepatoma.

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Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade

Cited by 76 publications

References 51 publications

17α-Estradiol arrests cell cycle progression at G2/M and induces apoptotic cell death in human acute leukemia Jurkat T cells

17α-Estradiol arrests cell cycle progression at G2/M and induces apoptotic cell death in human acute leukemia Jurkat T cells

Apoptosis of Human Jurkat T Cells Induced by the Methylene Chloride Extract from the Stems of Zanthoxylum schinifolium is Associated with Intrinsic Mitochondria-Dependent Activation of Caspase Pathway

Dulxanthone A induces cell cycle arrest and apoptosis via up‐regulation of p53 through mitochondrial pathway in HepG2 cells

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