Myc down‐regulation affects cyclin D1/cdk4 activity and induces apoptosis <i>via</i> Smac/Diablo pathway in an astrocytoma cell line

Amendola, Donatella; Salvo, Maria De; Marchese, Rodolfo; Falzacappa, Cecilia Verga; Stigliano, Antonio; Carico, Elisabetta; Brunetti, Ercole; Moscarini, Marina; Bucci, Barbara

doi:10.1111/j.1365-2184.2008.00576.x

Cited by 27 publications

(18 citation statements)

References 56 publications

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“…Likewise, we demonstrated this in two previous reports, as the modulation of this oncogene can also sensitize cells towards apoptosis in response to cytotoxic insults including chemotherapeutic agents and radiotherapy (38,39).…”

Section: Discussionsupporting

confidence: 80%

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines

Cerquetti

Sampaoli

Salvo

et al. 2015

International Journal of Oncology

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Abstract. C-MYC is overexpressed in many types of cancer linked to poor prognosis. We examined the c-Myc protein expression in adrenocortical cancer (ACC) cells to investigate the role of this protein in the neoplasm, its involvement in chemotherapy and finally to determine whether c-Myc could be considered a prognostic factor in patients with ACC. H295R and SW13 cell lines were treated with paclitaxel. c-Myc overexpressing cell clones were achieved by transfecting the H295R cell line with the pcDNA3-hMYC plasmid expressing the full-lengh C-MYC coding sequence. The SW13 cell line was transfected with siRNA oligonucleotides for C-MYC. Cell cycle analysis was evaluated by flow cytometry. c-Myc, cyclin B1 and pro caspase expression levels were evaluated by western blot analysis. We found that expression of c-Myc was highly expressed in the SW13 cells, whereas the protein was undetectable in the H295R cells. Different doses of paclitaxel were required in the two ACC cell line to induce a block in the G 2 phase, characterized by increased cyclin B1 levels and to induce apoptosis by procaspase-3 activation. Interestingly, the silencing of C-MYC mRNA prevented paclitaxel induced apoptosis in SW13 cells, whereas in the H295R cells the overexpression of C-MYC rendered the cells more prone to growth inhibition after paclitaxel exposure. The present study directly demonstrates that C-MYC plays a central role in controlling proliferation in ACC cells after paclitaxel treatment and that c-Myc could be considered as a marker for predicting response to chemotherapeutic agents in ACC cell lines. IntroductionAdrenocortical carcinoma (ACC) is a rare endocrine neoplasia with a variable prognosis, depending on tumor stage and time of diagnosis, but it is generally fatal, with an overall survival of 5 years from detection (1-3). Metastasis associated with ACCs can range from 30 to 85% (4).More recently, elevated or deregulated expression of the c-Myc protein has been detected in a wide range of human cancers, and is often associated with aggressive and poorly differentiated tumors. C-MYC belongs to the class of immediate early genes which are induced in response to a number of mitogenic signals. It encodes a nuclear transcription factor leading to activation or repression of target genes, thus affecting several biological processes, such as cellular growth, differentiation, cell cycle and apoptosis (5,6). Surprisingly, gene expression profile studies have demonstrated an underexpression of C-MYC in ACC compared to adrenocortical adenoma (7-10).The treatment with DNA-damaging agents can sensitize cells to apoptosis when c-Myc is overexpressed (11), but its role in cellular susceptibility to anticancer drugs is controversial. It has been reported that the overexpression of c-Myc not only enhances tumor cell sensitivity (12) but also induces resistance to antineoplastic agents (13).It has been widely demonstrated that cells expressing high c-Myc levels show an apoptosis-prone phenotype in response to different stimuli, affecting cell c...

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Section: Discussionsupporting

confidence: 80%

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines

Cerquetti

Sampaoli

Salvo

et al. 2015

International Journal of Oncology

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“…It has been reported that TGF-β down-regulates transcription factors involved in proliferation such as c-Myc (Warner et al, 1999). Previous studies have shown that c-Myc was a repressor of P27 (Amendola et al, 2009) and P15 (Staller et al, 2001) and that down-regulation of c-Myc would up-regulate these cyclin-dependent kinase inhibitors-again, results supported by the current in vivo analysis of increased intracellular signaling in the TGF-β pathway. Studies have shown that the activation of cyclin-dependent kinase inhibitors would lead to increased levels of pRB, consistent with the findings in the present study.…”

Section: Discussionsupporting

confidence: 75%

Smad2 Overexpression Reduces the Proliferation of the Junctional Epithelium

2014

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The overexpression of the intracellular signaling molecule of the transforming growth factor-beta family (TGF-β) Smad2 was found to induce apoptosis and inhibit the proliferation rate of oral epithelial cells. Therefore, the aim of this study was to investigate in vivo the effect of Smad2 overexpression on the proliferation rate of the junctional epithelium (JE). Smad2 overexpression was driven by the cytokeratin 14 promoter (K14-Smad2) in transgenic mice. The K14-Smad2 mice were compared with wild-type (WT) mice selected as the control group. Samples were stained with hematoxylin and eosin stains and analyzed by image analysis. Immunohistochemistry was conducted for proliferating cell nuclear antigen (PCNA) and c-Myc as markers of cell proliferation. The expression of cyclin-dependent kinase inhibitors (P15, P21, and P27) was determined by real-time polymerase chain-reaction (RT-PCR). The quantity of phosphorylated retinoblastoma (pRB) was determined with Western blots. The overexpression of Smad2 altered the area of the junctional epithelial cells in one-yearold K14-Smad2 mice. The area was 32,768 (± 3,473) μm 2 for the WT and 24,937.25 (± 1,965) μm 2 for the K14-Smad2 mice. There was a significant difference in the proliferation rates of the JE (PCNA-positive cells) between the WT and K14-Smad2 mice, 20.7% (± 1.1) and 2.1% (± 0.5), respectively. A significant difference in c-Myc expression occurred between experimental and control samples. The K14-Smad2 mice had a mean of 2.3% (± 0.6), and the WT mice had a mean of 20.1% (± 3.6). Smad2 overexpression up-regulated the mRNA expression of P15 by 2.3-fold and that of P27 by 5.5-fold in the K14-Smad2 mice. Finally, the pRB protein showed a 2.3 (± 0.5)-fold increase in K14-Smad2 mice when compared with WT mice. Smad2 overexpression inhibits the proliferation of JE cells by down-regulating c-Myc and up-regulating P15 and P27, which resulted in an increase in pRB, leading to cell-cycle arrest.

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“…Amla extract suppressed Wnt/β-catenin signalling by suppressing nuclear transport of β-catenin and downregulated β-catenin target proteins c-Myc and cyclin D1, which explains suppressed HCCSC proliferation and stem-ness (Amendola et al, 2009). Furthermore, efficacy of amla extracts was similar to cytotoxic drug FU.…”

Section: Fig 4 -Effect Of Methanol Extract Of Amla Seed (As) or Pulpmentioning

confidence: 97%

Indian gooseberry (Emblica officinalis Gaertn.) suppresses cell proliferation and induces apoptosis in human colon cancer stem cells independent of p53 status via suppression of c-Myc and cyclin D1

Vadde

Radhakrishnan

Kurundu

et al. 2016

Journal of Functional Foods

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Available online A B S T R A C TIndian gooseberry, also known as amla, a widely consumed fruit in South Asia, was evaluated for its anti-proliferative and pro-apoptotic mechanisms on human colon cancer stem cells (HCCSC). Amla extracts suppressed proliferation and induced apoptosis independent of p53, a tumour suppressor gene, in HCCSCs. Further, amla extracts suppressed cell proliferation by targeting the Wnt/β-catenin signalling pathway as seen by decreased nuclear translocation of β-catenin. Additionally, this led to suppressed expression of c-Myc and cyclin D1, key proteins involved in cell proliferation. Inhibition of stem-ness of HCCSCs by amla may be due to its effect on the Wnt/β-catenin signalling. These results indicate that amla suppresses HCCSC proliferation and induces apoptosis independent of p53 status via potentially targeting Wnt/β-catenin signalling pathway. Amla is therefore a promising functional food for preventing colon cancer and might be a novel resource for the food industry.

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Myc down‐regulation affects cyclin D1/cdk4 activity and induces apoptosis via Smac/Diablo pathway in an astrocytoma cell line

Abstract: Our results suggest that c-Myc could be considered as a good target for the study of new approaches in anticancer astrocytoma treatment.

Cited by 27 publications

References 56 publications

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines

Smad2 Overexpression Reduces the Proliferation of the Junctional Epithelium

Indian gooseberry (Emblica officinalis Gaertn.) suppresses cell proliferation and induces apoptosis in human colon cancer stem cells independent of p53 status via suppression of c-Myc and cyclin D1

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