Ursolic Acid Triggers Apoptosis and Bcl-2 Downregulation in MCF-7 Breast Cancer Cells

Kassi, Eva; Sourlingas, Thomae G.; Spiliotaki, Maria; Papoutsi, Zoi; Pratsinis, Harris; Aligiannis, Nektarios; Moutsatsou, Paraskevi

doi:10.1080/07357900802672712

Cited by 111 publications

(86 citation statements)

References 47 publications

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“…Research has confirmed that p53 is an important regulator of apoptosis, and its interaction with Bcl-2 or Bcl-XL results in the assembly of pro-apoptotic proteins Bax and Bak in the mitochondrial membrane to form pores, which finally causes the release of cytochrome c and other apoptotic activators from the mitochondria (37). It was reported that the mitochondrial pathway (also called the intrinsic pathway) of apoptosis is inhibited or triggered by anti-apoptotic proteins such as Bcl-2 and Bcl-xL or pro-apoptotic proteins such as Bax, Bak, Bim and Bid (38). In the present study, the downregulation of Bcl-2 expression, and the synchronously upregulated expression of Bim and Bax in the U87MG and T87G cells probably contributed to the release of cytochrome c and the following apoptotic events, which is similar to previous studies in human gastric tumor cells and breast cancer cells (14,15).…”

Section: Discussionmentioning

confidence: 99%

Dracorhodin perchlorate induces the apoptosis of glioma cells

et al. 2016

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Abstract. Dracorhodin perchlorate (Dp), a synthetic analogue of the antimicrobial anthocyanin red pigment, has recently been shown to induce apoptotic cell death in various types of cancer cells. Yet, the inhibitory effect of Dp on human glioma cells remains uninvestigated. Therefore, in the present study, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were used to detect cell viability and cell cycle progression in glioma U87MG and T98G cells, respectively. Annexin V-FITC/propidium iodide double staining and JC-1 staining were separately applied to determine cellular apoptosis and mitochondrial membrane potential damage in the cells. The expression levels of associated proteins involved in cell cycle progression and apoptosis were measured by western blotting. The activities of caspase-9/-3 were determined by Caspase-Glo-9/3 assay. The results indicated that Dp treatment significantly inhibited cell proliferation in a dose-and time-dependent manner, and blocked cell cycle progression at the G 1 /S phase in the U87MG and T98G cells via the upregulation of p53 and p21 protein expression, and simultaneous downregulation of Cdc25A, Cdc2 and P-Cdc2 protein expression. Additionally, Dp treatment led to the loss of cellular mitochondrial membrane potential, and the release of cytochrome c, and strongly induced the occurence of apoptosis. Increased expression levels of Bim and Bax protein and the downregulated expression of Bcl-2 protein were observed. Caspase-9/-3 were activated and their activities were elevated after Dp treatment. These findings indicate that Dp inhibits cell proliferation, induces cell cycle arrest and apoptosis in glioma cells, and is a possible candidate for glioma treatment. IntroductionBrain glioma is the most common form of neural malignancy in the nervous system. High grade glioma is the leading cause of brain cancer-related mortality due to its high invasive ability and malignant proliferation (1,2). Glioma incidence accounts for approximately 40-50% of all intracranial tumors (3). Although current treatment has modestly improved patient survival, patients with gliomas still have a very poor prognosis and low cure rates. It was reported that patients with anaplastic astrocytoma have a median survival of 2-3 years, but for those with more aggressive glioblastomas, the median survival is only 12-15 months (4,5). Currently, surgery is considered as an important initial clinical approach for glioma, yet it is difficult to completely remove diffuse tumor cells. Radiotherapy and chemotherapy after initial surgical resection are regarded as an effective therapeutic plan to prevent disease recurrence (6). However, most attempts to increase the efficacy of radiotherapy and chemotherapy are hampered by unacceptable late toxicities (7). In addition, the drug-resistance of tumor cells finally results in the abrogation of the effects of current chemotherapeutic agents (8). Accordingly, to improve the prognosis and quality of life of patients with gliomas, the ...

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Section: Discussionmentioning

confidence: 99%

Dracorhodin perchlorate induces the apoptosis of glioma cells

et al. 2016

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“…In particular, the interaction between Bax and Bcl‐2 leads to a loss of mitochondrial membrane potential. As a result, mitochondrial cytochrome c is released into the cytoplasm from the mitochondria and activates the caspase pathways (Dong et al., 2014; Kassi et al., 2009). In our study, OJE‐treated cells did not exhibit dramatically altered Bax mRNA levels, but the Bcl‐2 levels were certainly decreased at the highest treatment concentration (50 μg/ml).…”

Section: Resultsmentioning

confidence: 99%

Orostachys japonicus induce p53‐dependent cell cycle arrest through the MAPK signaling pathway in OVCAR‐3 human ovarian cancer cells

Lee

Kim

Lee

2018

Food Science & Nutrition

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Orostachys japonicus (O. japonicus) is utilized as a traditional medicine for patients with various diseases. This study investigated the effect of the ethyl acetate fraction from O. japonicus extract (OJE) on the growth inhibition of OVCAR‐3 human ovarian cancer cells demonstrated to inhibit cell growth and arrest the cell cycle in OVCAR‐3 cells by blocking the sub‐G1 phase and decreasing cyclin E1/CDK2 expression. Cell cycle arrest was connected to the increased expression of the cell cycle regulating factors p53 and p21. Apoptosis was initiated through the intrinsic pathway by up‐regulating the expression of the Bcl‐2/Bax ratio and down‐regulating the expression of pro‐caspase‐3. Furthermore, OJE treatment elicited p‐p38 activation and p‐ERK1/2 inhibition. In conclusion, our results demonstrated that OJE reduced the growth of OVCAR‐3 human ovarian cancer cells mediated by arrest of the cell cycle and regulation of MAPK signaling pathways.

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“…A natural compound, the pentacyclic triterpenoid ursolic acid (UA) (3 b-hydroxy-urs-12-en-28-oic-acid) (Liu 1995), has been reported to be a potent inhibitor of constitutive and inducible STAT3 as well as NF-jB activation in prostate cancer cells ). The authors also showed that UA significantly suppressed the growth of prostate cancer xenografts in vivo while it was previously reported to be able to inhibit tumor promotion, metastasis, angiogenesis and proliferation of a variety of tumor cells, including human multiple myeloma cells ) melanoma cells (Manu and Kuttan 2008) and breast cancer cells (Kassi et al 2009). Predictive analysis using a virtual tumor cell platform that allows for the determining of the primary target of UA in the prostate cancer cells showed that UA mediates an increase in the apoptotic phenotype by inhibiting STAT3 as well as NF-jB activity.…”

Section: Prostate Cancermentioning

confidence: 88%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor-and cytokine-membrane receptors including interferon and interleukin, or by nonreceptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.The family of STAT transcription factors Structure and function STAT (signal transducers and activators of transcription) proteins were originally described as a family of cytoplasmic transcription factors. In mammals, seven members of this family, each consisting of 750-900 amino acids, have been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. These transcription factors act as dimers (homo-or hetero-dimers), and their activation is dependent on their phosphorylation or via membrane receptors stimulated by either extracellular factors, including interferon (IFN) and interleukin (IL-6), or by intracellular kinases independent of receptors, including Src. Activation of STATs is usually transient and highly regulated. STAT proteins contain seven conserved structural and functional domains ( First, the amino terminal NH 2 domain is involved in the dimerization of STAT proteins and in the stabilization of the interaction established between these dimers and DNA response elements (Braunstein et al. 2003;Mertens et al. 2006). The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al. 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes. With the exception of STAT2, all activated STAT homodimers bind directly to a palindromic sequence, the GAS (IFN-gammaactivated site), TTTCCNGGAAA (Becker et al. 1998). The ''linker'' domain localizes the active dimer to the DNA binding site. The transcriptional activation domain (TAD) contains sites of phosphorylation of serine residues that allow the recruitment of coactivators such as RNA polymerase II, histone acetyltransferase (HAT) (Paulson et al. 2002), histone deacetylase (HDAC) (Rascle et al. 2003) and chromatin modification complexes.Finally, two sites are particularly critical for the activity of STAT. These are the SH2 domain (Src homology 2, amino acids 575-680), which is linked to the DBD by the linker domain, and a conser...

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Ursolic Acid Triggers Apoptosis and Bcl-2 Downregulation in MCF-7 Breast Cancer Cells

Cited by 111 publications

References 47 publications

Dracorhodin perchlorate induces the apoptosis of glioma cells

Dracorhodin perchlorate induces the apoptosis of glioma cells

Orostachys japonicus induce p53‐dependent cell cycle arrest through the MAPK signaling pathway in OVCAR‐3 human ovarian cancer cells

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

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