Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

Kim, Hak-Ryul; Kim, Eun-Jung; Yang, Sei‐Hoon; Jeong, Eun Taik; Park, Channy; Lee, Jae Hyung; Youn, Myung-Ja; So, Hong-Seob; Park, Raekil

doi:10.1038/emm.2006.73

Cited by 66 publications

(46 citation statements)

References 33 publications

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“…The t-Bid could translocate to mitochondria and initiate the intrinsic pathway. 20 The activation of intrinsic pathway was confirmed by the collapse of mitochondrial membrane potential and the release of cytochrome c and AIF on UA-treated R-HepG2 cells (Fig. 4B and C).…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 73%

“…The truncated t-Bid could translocate to mitochondria and induce cytochrome c release, ultimately leading to cell death. 20 UA induced activation of intrinsic apoptotic pathway on R-HepG2 cells. Mitochondrial dysfunction plays a critical role in the induction and execution of apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…Some researches demonstrated that extrinsic and intrinsic pathways could be linked by the cleavage of pro-apoptotic protein Bid by caspase-8. 20 In our study, after UA treatment activated caspase-8 triggered the cleavage of Bid to t-Bid (Fig. 3).…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

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Anti-Proliferative effect of ursolic acid on multidrug resistant hepatoma cells R-HepG2 by apoptosis induction

Zhang¹,

Tang²,

Chan³

et al. 2007

Cancer Biology & Therapy

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Many studies have demonstrated that ursolic acid (UA) could potently inhibit the proliferation of a wide variety of cancer cells; however, its anti-tumor effect on multidrug resistant carcinoma was rarely reported. In the present study, UA exhibited cytotoxicity on the multidrug resistant human hepatoma cell line R-HepG2 with the IC 50 value of 20 mM at 48 h. Our findings indicated that UA was not a binding substrate for P-glycoprotein and could not modulate the expression and activity of P-glycoprotein. This provided a possible mechanism on UA circumvention of the drug resistance. Mechanistic study demonstrated that UA induced apoptosis on R-HepG2 cells via both extrinsic and intrinsic apoptotic pathways, including the activation of caspase cascade and the release of cytochrome c and AIF from mitochondria to cytosol. Furthermore, in vivo study showed a significant inhibition on the growth of R-HepG2 cells in the UA-treated group (30 mg/kg/day, i.v.), with negligible damage towards the heart and the liver. The present study suggests the potential of UA as chemotherapeutic agent and provides further insight into the molecular basis of UA-induced apoptosis on multidrug resistant human hepatoma cells.

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Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

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Anti-Proliferative effect of ursolic acid on multidrug resistant hepatoma cells R-HepG2 by apoptosis induction

Zhang¹,

Tang²,

Chan³

et al. 2007

Cancer Biology & Therapy

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“…In myocytes, Hopx can also interact with histone deacetylase 2 and recruits it to SRF-Hopx complexes [51]. Interestingly, histone deacetylase inhibitors have been reported to activate apoptotic pathways including Fas-mediated apoptosis [52][53][54][55] and exhibit therapeutic potential in the treatment of cancer [56,57] and inflammatory diseases [58,59]. In skeletal muscle cells, Hopx is expressed as well, but acts independently of SRF and mostly activates transcription of the target genes [60].…”

Section: Discussionmentioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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“…Many HDIs such as TSA and apicidin have been shown to inhibit tumor growth through upregulating the cell cycle inhibitor p21 or blocking neovascularization by lowering VEGF levels and altering the VEGF-mediated signal pathway in vivo and in vitro models (Deroanne et al, 2002;Sawa et al, 2002;Liu et al, 2003;Kim et al, 2006). Hence, understanding the TSA-regulated TSP-1 expression and the effects of TSA-induced TSP-1 on cellular function could present insights into the mechanism of action of TSA in anti-tumorigenesis, and might suggest a novel approach to cancer therapy.…”

Section: Genesismentioning

confidence: 99%

Inhibition of trichostatin A-induced antiangiogenesis by small-interfering RNA for thrombospondin-1

Kang

Kim²,

Chang³

et al. 2007

Exp Mol Med

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Abbreviations: BAE, bovine aortic endothial cell; HDI, histone deacetylase inhibitor; pTSP-Luc, luciferase reporter plasmid containing TSP-1 promoter region; siRNA, small interfering RNA; TSA, trichostatin A; TSP-1, thombospondin-1; V-DMSO, empty vector-transfected BAE cell in the presence of DMSO AbstractExpression of thrombospondin-1 (TSP-1), which is a known inhibitor of tumor growth and angiogenesis, is reciprocally regulated by positive regulators, such as VEGF. Additionally, trichostatin A (TSA) suppresses tumor progression by altering VEGF levels and VEGF-mediated signaling. Thus, understanding TSA-regulated TSP-1 expression and the effects of altered TSP-1 levels might provide insights into the mechanism of action of TSA in anti-tumorigenesis, and provide an approach to cancer therapy. Here, we examined the effect of TSA on TSP-1 expression, and the effects of TSA-induced TSP-1 on cell motility and angiogenesis, in HeLa and bovine aortic endothelial cells. TSA remarkably increased TSP-1 expression at the mRNA and protein levels, by controlling the TSP-1 promoter activity. Both TSA and exogenous TSP-1 reduced cell migration and capillary-like tube formation and these activities were confirmed by blocking TSP-1 with its neutralizing antibody and small-interfering RNA. Our results suggest that TSP-1 is a potent mediator of TSA-induced antiangiogenesis.

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Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

Cited by 66 publications

References 33 publications

Anti-Proliferative effect of ursolic acid on multidrug resistant hepatoma cells R-HepG2 by apoptosis induction

Anti-Proliferative effect of ursolic acid on multidrug resistant hepatoma cells R-HepG2 by apoptosis induction

Persistence of effector memory Th1 cells is regulated by Hopx

Inhibition of trichostatin A-induced antiangiogenesis by small-interfering RNA for thrombospondin-1

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