Survivin and p53 Modulate Quercetin-induced Cell Growth Inhibition and Apoptosis in Human Lung Carcinoma Cells

Kuo, Pao Chen; Liu, Huei Fang; Ji, Chao

doi:10.1074/jbc.m407985200

Cited by 172 publications

(128 citation statements)

References 40 publications

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“…The lack of response to apoptotic stimuli results in tumor growth and progression as well as resistance to most oncologic therapies [17]. It has been reported that the inhibition of apoptosis induces mitotic progression in cancer cells [18]. The suppression of apoptosis is considered one of the possible mechanisms of tumor progression, and many anti-cancer treatments act through their induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of KDR expression induces apoptosis in breast cancer cells

Zhang

Yan

et al. 2014

Cellular and Molecular Biology Letters

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Angiogenesis plays a crucial role in the growth, invasion and metastasis of breast cancer. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are the key regulators of tumor angiogenesis. VEGFR-2, known as the kinase insert domain receptor (KDR), is a key receptor involved in malignant angiogenesis. We previously showed that knocking down KDR with short interference RNA (KDR-siRNA) markedly decreased KDR expression and suppressed tumor growth in a xenograft model. However, the mechanisms underlying the anti-cancer effects of KDR-siRNA are not clearly understood. This study aimed to elucidate the molecular mechanisms that induce apoptosis in human breast cancer MCF-7 cells after transfection with KDRsiRNA. We studied the effects of KDR-siRNA on proliferation, apoptosis, antiapoptotic and pro-apoptotic proteins, mitochondrial membrane permeability, cytochrome c release and caspase-3 activity. The results indicated that KDRsiRNA treatment significantly inhibited the proliferation and induced the apoptosis of MCF-7 cells, reduced the levels of the anti-apoptotic proteins, Bcl-2 and Bcl-xl, and increased the level of the pro-apoptotic protein Bax, resulting in a decreased Bcl-2/Bax ratio. KDR-siRNA also enhanced the mitochondrial membrane permeability, induced cytochrome c release from the mitochondria, upregulated apoptotic protease-activating factor-1 (Apaf-1), cleaved caspase-3, and increased caspase-3 activity in MCF-7 cells. Furthermore, KDR-siRNA-induced apoptosis in MCF-7 cells was blocked by the caspase inhibitor Z-VAD-FMK, suggesting a role of caspase activation in the induction of apoptosis. These results indicate that the Bcl-2 family proteins and caspase-related mitochondrial pathways are primarily involved in KDR-siRNAinduced apoptosis in MCF-7 cells and that KDR might be a potential therapeutic target for human breast cancer treatments.

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Section: Discussionmentioning

confidence: 99%

Downregulation of KDR expression induces apoptosis in breast cancer cells

Zhang

Yan

et al. 2014

Cellular and Molecular Biology Letters

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“…The main procedure was according to our previous study (32). After treatment with or without baicalein, the cells were fixed in 4% paraformaldehyde solution in PBS for 1 h at 37jC.…”

Section: Cell Number Assaymentioning

confidence: 99%

“…Western Blot Analysis The total cellular protein extracts were prepared as described (32). Western blot analyses of cyclin B1, CDC2, phospho-CDC2, survivin, p38, phospho-p38, AKT, phospho-AKT, BCL-2, XIAP, and extracellular signalregulated kinase-2 were done using specific antibodies.…”

Section: Cell Number Assaymentioning

confidence: 99%

Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT

Liu

2007

Molecular Cancer Therapeutics

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128

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The bioactive flavonoid baicalein has been shown to have in vitro growth-inhibitory activity in human cancer cells, although the mechanism of action is poorly understood. Baicalein (40 -80 Mmol/L for 24 h) more effectively induced cytotoxicity compared with other flavonoids (baicalin, catechin, genistein, quercetin, and rutin) in bladder cancer cells. Baicalein induced cell proliferation inhibition and apoptosis. The levels of cyclin B1 and phospho-CDC2 (Thr 161 ) were reduced, whereas the G 2 -M phases were elevated by baicalein. Treatment of CDC2 kinase or CDC25 phosphatase inhibitors augments the baicalein-induced cytotoxicity. A variety of human bladder cancer cell lines expressed survivin proteins, which were located on the mitotic phases and regulated mitotic progression. Baicalein markedly reduced survivin protein expression. Transfection of a survivin small interfering RNA diminished the level of survivin proteins and increased the baicalein-mediated cell death. Overexpression of survivin enhanced cell proliferation and resisted the baicalein-induced cytotoxicity. Interestingly, baicalein induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AKT. SB203580, a specific p38 MAPK inhibitor, attenuated proliferation inhibition and restored the protein levels of phospho-CDC2 (Thr 161 ) and survivin in the baicalein-exposed cells; conversely, blockade of AKT activation enhanced cytotoxicity and the reduction of phospho-CDC2 (Thr 161 ) and survivin proteins.As a whole, these findings provide that the opposite role of p38 MAPK and AKT regulates CDC2 kinase and survivin and the inhibition of CDC2-survivin pathway by baicalein contributes to apoptosis and proliferation retardation in cancer cells.

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“…In addition, Gudkov et al showed that PFT-a protected mice from the lethal genotoxic stress associated with cancer treatment without promoting the formation of tumors. As this compound was shown in subsequent in vitro and in vivo studies to protect different cell types against p53-dependent apoptosis induced by a multitude of stimuli, [5][6][7][8][9][10][11] PFT-a was considered a specific p53 inhibitor and was therefore commonly used to distinguish p53-dependent and -independent apoptosis systems. However, only a few studies applied PFT-a onto p53-deficient cells to unambiguously show its specificity in their systems.…”

mentioning

confidence: 99%

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

et al. 2009

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Pifithrin-a (PFT-a) was shown to specifically block transcriptional activity of the tumor suppressor p53 and was therefore proposed to be useful in preventing the severe side effects often associated with chemo-and radiotherapy. We report here that although PFT-a efficiently protected different cell types from DNA damage-induced apoptosis, it mediated this effect regardless of the presence or absence of p53. Interestingly, PFT-a blocked the apoptosome-mediated processing and activation of caspase-9 and -3 without interfering with the activation of mitochondria. Neither the DNA damage-induced activation of Bax or Bak nor the loss of the mitochondrial membrane potential or the final release of cytochrome c were inhibited by this compound. Instead, the ability of PFT-a to protect p53-deficient cells from DNA damage-induced caspase activation and apoptosis was greatly diminished after siRNA-mediated downregulation of cyclin-D1 expression. In contrast, downregulation of other proteins involved in cell-cycle progression, such as the retinoblastoma protein, cyclin D3, as well as the cyclin-dependent kinases, 2, 4 and 6, could not abolish this protection. Thus, our data show that PFT-a protects cells from DNA damage-induced apoptosis also by a p53-independent mechanism that takes place downstream of mitochondria and that might involve cyclin D1.

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Survivin and p53 Modulate Quercetin-induced Cell Growth Inhibition and Apoptosis in Human Lung Carcinoma Cells

Cited by 172 publications

References 40 publications

Downregulation of KDR expression induces apoptosis in breast cancer cells

Downregulation of KDR expression induces apoptosis in breast cancer cells

Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

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