Inactivation of PI3k/Akt signaling pathway and activation of caspase-3 are involved in tanshinone I-induced apoptosis in myeloid leukemia cells in vitro

Liu, Jiajun; Liu, Wenda; Yang, Hongzhi; Zhang, Yong; Fang, Zhigang; Liu, Peiqing; Lin, Dong‐Jun; Xiao, Ran; Hu, Yuan; Wang, Chunzhi; Li, Xudong; He, Yi; Huang, Ruxun

doi:10.1007/s00277-010-0996-z

Cited by 59 publications

(34 citation statements)

References 41 publications

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“…[32][33][34][35][36][37][38][39] SVV is unique relative to other inhibitor of apoptosis proteins because of three distinct features (reviewed by Ouhtit et al 32 ) as follows: i) SVV expression is virtually absent in a majority of normal adult tissues, however, it is overexpressed in many human tumors, ii) SVV contains a baculovirus inhibitor of apoptosis proteins repeat domain that interacts with and inhibits the pro-apoptotic functions of caspases, and iii) SVV is the only inhibitor of apoptosis protein tightly regulated throughout cell-cycle progression. The dual role in inhibiting apoptosis and contributing to cellular proliferation makes SVV an attractive molecular target and a promising lead for BC therapy.…”

Section: Discussionmentioning

confidence: 99%

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Abdraboh

Gaur

Hollenbach

et al. 2011

The American Journal of Pathology

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The hyaluronan (HA) receptor CD44 plays an essential role in cell-cell or cell-extracellular matrix communications and is a bioactive signal transmitter. Although a number of studies have described the function of CD44 in breast cancer (BC) metastasis, the underlying mechanisms have yet to be determined. By using a validated tetracycline-off-regulated CD44 expression system in the MCF-7 cell line combined with microarray analysis, we identified survivin (SVV) as a potential downstream transcriptional target of CD44. To test the hypothesis that SVV underpins CD44-promoted BC cell invasion, we combined molecular and pharmacologic approaches and showed that CD44 induction increased SVV expression levels, which in turn promotes BC cell invasion. Further, clinical analysis of breast tissue samples showed that SVV expression patterns paralleled those of the standard form of CD44 during breast tumor progression. More interestingly, we identified the PI3K/E2F1 pathway as a potential molecular link between HA/CD44 activation and SVV transcription. In addition to identifying SVV as a target for HA/CD44 signaling, this investigation provides a better understanding of the molecular mechanisms that underpin the novel function of SVV in breast cancer metastasis. Breast cancer (BC) is the most common cancer and the second most common cause of cancer-related deaths in women in the United States, with more than 175,000 women being diagnosed annually. 1,2 In the later stages of progression, BC cells metastasize from the original tumor site and travel through the vasculature to distant organs such as liver, lungs, brain, and bone. [2][3][4][5] Although the involvement of cell adhesion molecules in cancer development, progression, and metastasis has been established and discussed extensively in the literature, the mechanisms underlying their implication is still nascent. 6 -9 The hyaluronan (HA) receptor CD44, a multistructural and multifunctional cell adhesion molecule involved in cell-cell and cell-extracellular matrix interactions, functions as a bioactive signaling transmitter involved in a variety of cellular responses, including lymphocyte homing, hematopoiesis, inflammation, tumorigenesis, angiogenesis, and metastasis. 10 -13 The CD44 -HA complex initiates a series of intracellular signaling events that lead to migration, adhesion, invasion, proliferation, and differentiation of a variety of cells. The transduction of HA/CD44 signaling can occur through various mechanisms including the following: i) HA binding to CD44 can initiate the extracellular clustering of CD44, resulting in the activation of downstream kinases, 14 ii) CD44 can serve as a co-receptor physically associated with other cell signaling receptors, [15][16][17][18] iii) CD44 can serve as a docking protein for pericellular or cytoplasmic proteins, 19,20 and iv) the transmembrane domain of CD44 can be cleaved, allowing the translocation of the cytoplasmic domain to the nucleus, where it functions as a transcription factor regulating the expression of target gen...

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Section: Discussionmentioning

confidence: 99%

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Abdraboh

Gaur

Hollenbach

et al. 2011

The American Journal of Pathology

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“…Cell lysates were measured for protease activity using a caspasespecific peptide conjugated with the color molecule ρNA. The caspase-cleaved chromophore ρNA was quantitated with a spectrophotometer at a wavelength of 405 nm [27] .…”

Section: Apoptosis Assaymentioning

confidence: 99%

Ginsenoside Rh2 inhibits glioma cell proliferation by targeting microRNA-128

et al. 2011

Acta Pharmacol Sin

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Aim: To examine the influence of ginsenoside Rh2 (Rh2), a triterpene saponin extracted from the traditional medicinal plant ginseng, on the expression of miRNAs in human glioma cells. Methods: The expression profile of miRNA (miR) was analyzed in human U251, T98MG and A172 glioma cells using a miRNA array and quantitative real-time PCR. Cell viability was assessed using a colorimetric assay (cell counting kit-8). Transfection of miR-128 was performed using Lipofectamine 2000. Caspase 3 activity was determined using a caspase colorimetric assay kit. Apoptosis was assessed using annexin V and propidium iodide staining. Protein expression was determined with Western blot analysis. miRNA-128 targeting activity was measured using a luciferase reporter assay. Results: In U251 cells treated with Rh2 (12 μg/mL), 14 of 452 human miRNAs were up-regulated and 12 were down-regulated as detected with the miRNA array assay. The up-regulation of miR-128 by Rh2 was further verified in human U251, T98MG and A172 cells using quantitative real-time PCR. In U251 cells, transfection of a miR-128 inhibitor (50 nmol/L) prevented the overexpression of miR-128 by Rh2, and significantly blunted Rh2-induced cytotoxicity, apoptosis, caspase 3 activation, transcriptional activation of E2F3a, a miR-128 target gene, as well as E2F3a protein expression. Conclusion: The anti-proliferative effect of Rh2 in human glioma cells was mediated in part through up-regulation of miRNA-128 expression.

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“…Ursolic acid, a naturally occurring triterpenoid, induces the apoptosis of human cancer cells through multiple signaling pathways (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). In studies on the pro-apoptotic role of ursolic acid in urinary system cancer, prostate cancer cells are usually targeted and the apoptotic signaling pathways have been shown to be activated by ursolic acid.…”

Section: Introductionmentioning

confidence: 99%

Ursolic acid induces apoptosis via Akt/NF-κB signaling suppression in T24 human bladder cancer cells

Gai¹,

Cai²,

Wang³

et al. 2013

Molecular Medicine Reports

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The Akt/NF-κB pathway is involved in numerous anti‑apoptotic and drug resistance events which occur in various types of bladder cancer. The present study investigated the role of ursolic acid in the regulation of anti-apoptotic Akt and NF-κBp65 signaling. T24 human bladder cancer cells were treated with ursolic acid at final concentrations of 12.5, 25 or 50 µmol/l for 48 h. Quantitative PCR (qPCR) and western blotting were performed to detect mRNA and protein expression, respectively. The results showed that anti-apoptotic phospho-Akt1 (pAkt1), phospho-IκBα (pIκBα), NF-κBp65 and Bcl-2 were inhibited and pro-apoptotic caspase-3 was upregulated in a dose‑dependent manner. A 50 µmol/l dose of ursonic acid decreased the mRNA expression levels of anti-apoptotic NF-κBp65 and Bcl-2 0.17 (8.9/52.6)-fold and 0.22 (9.5/42.3)‑fold, respectively. The pro-apoptotic caspase-3 mRNA expression levels were upregulated 4.78 (38.7/8.1)-fold. The anti-apoptotic pAkt1, pIκBα, NF-κBp65 and Bcl-2 protein levels were downregulated to 5.1 (blot grayscales vs. control at 32.3), 3.2 (vs. 24.2), 8.5 (vs. 45.1) and 9.2 (vs. 40.3). The protein levels of pro-apoptotic caspase-3 were upregulated to 20.7 (vs. 4.7). The proliferative activity of T24 cells treated with 12.5, 25.0 and 50.0 µmol/l ursolic acid was significantly reduced compared with that of control cells (83.8, 56.2 and 31.5 vs. 97.6%, respectively, P<0.05 for each). In conclusion, ursolic acid is important in inducing apoptosis via the suppression of Akt/NF-κB signaling in T24 human bladder cancer cells and this occurs in a dose-dependent manner. Ursolic acid may therefore serve as a naturally occurring candidate drug for the prevention and treatment of bladder cancer.

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Inactivation of PI3k/Akt signaling pathway and activation of caspase-3 are involved in tanshinone I-induced apoptosis in myeloid leukemia cells in vitro

Cited by 59 publications

References 41 publications

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Ginsenoside Rh2 inhibits glioma cell proliferation by targeting microRNA-128

Ursolic acid induces apoptosis via Akt/NF-κB signaling suppression in T24 human bladder cancer cells

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