Aberrant Expression of Fra-1 in Estrogen Receptor-negative Breast Cancers and Suppression of their Propagation In Vivo by Ascochlorin, an Antibiotic that Inhibits Cellular Activator Protein-1 Activity

Nakajima, Hiroo; Mizuta, Naruhiko; Sakaguchi, Kôichi; Fujiwara, Ikuya; Mizuta, Mitsuhiko; Furukawa, Chiharu; Chang, Young‐Chae; Magae, Junji

doi:10.1038/ja.2007.87

Cited by 20 publications

(18 citation statements)

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“…Several studies have described the effect of increased Fra-1 expression in several tumor entities (Chiappetta et al 2000(Chiappetta et al , 2007Debinski and Gibo 2005;Kustikova et al 1998; Logullo et al 2011;Nakajima et al 2007;Song et al 2006;Usui et al 2012;Zajchowski et al 2001). In breast cancer cell lines, overexpression of this transcription factor leads to morphological changes, increased motility and invasive behavior in vitro (Belguise et al 2005;Milde-Langosch 2005;Milde-Langosch et al 2004).…”

Section: Discussionmentioning

confidence: 95%

“…The expression of Fra-1 is deregulated in many tumors (MildeLangosch 2005): its overexpression has been reported in proliferative disorders such as breast, brain, lung, colon, esophageal and thyroid cancer (Belguise et al 2005;Chiappetta et al 2000Chiappetta et al , 2007Debinski and Gibo 2005;Kustikova et al 1998;Logullo et al 2011;Nakajima et al 2007;Song et al 2006;Usui et al 2012;Young and Colburn 2006;Zajchowski et al 2001). In addition, Fra-1 expression has been shown as a feature of hyperplastic and neoplastic breast epithelium (Chiappetta et al 2007;Nakajima et al 2007;Song et al 2006) with capacity to influence proliferation, migration and invasiveness of breast cancer cells (Belguise et al 2005;Kustikova et al 1998). These findings implicate that Fra-1 activity might be functionally involved in breast cancer metastasis.…”

Section: Introductionmentioning

confidence: 96%

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Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties

Oliveira‐Ferrer

Kürschner

Labitzky

et al. 2015

J Cancer Res Clin Oncol

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 96%

Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties

Oliveira‐Ferrer

Kürschner

Labitzky

et al. 2015

J Cancer Res Clin Oncol

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“…ASC acts through a range of receptors and regulatory proteins exerting diverse effects on various cell types. For example, ASC suppresses oxidized low density lipoprotein (oxLDL)-induced MMP-9 expression by inhibiting the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway in human THP-1 macrophages (2, 3), suppresses the activator protein-1 (AP-1) activity of estrogen receptor-negative human breast cancer cells, partly due to induction of apoptosis (4), and promotes activation of p53 and inhibition of mitochondrial respiration (5). Recent results show that ASC inhibits mitochondrial electron transport by binding to cytochrome bc1.…”

Section: Ascochlorin (Asc)mentioning

confidence: 99%

4-O-Carboxymethyl Ascochlorin Causes ER Stress and Induced Autophagy in Human Hepatocellular Carcinoma Cells

Kang

Chang

Maurizi

2012

Journal of Biological Chemistry

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Background: 4-O-Carboxymethyl ascochlorin (AS-6), a PPAR␥ agonist, reduces serum glucose levels in a diabetic mouse model. Results: Proteomics analysis revealed that many proteins up-regulated after AS-6 treatment were associated with ER stress response. Conclusion: AS-6 produces an ER unfolded protein response, inducing autophagy, and activating transcription factor CHOPdependent apoptosis. Significance: By stimulating autophagy, AS-6 might be effective in blocking proliferation of cancer cells.

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“…We also found that human breast cancer cell lines that are devoid of estrogen receptors exhibit higher AP-1 activity and express higher levels of c-Jun, c-Fos and Fra-1 compared with estrogen receptor-positive human breast cancer cell lines and that ascochlorin selectively kills estrogen receptor-negative breast cancer cells, partly through the induction of apoptosis. 17,18 The p53 tumor suppressor protein is involved in multiple central cellular processes, including transcription, DNA repair, genetic stability, senescence, cell cycle control and apoptosis. [19][20][21] It is functionally inactivated by structural mutations, interaction with viral products and endogenous cellular mechanisms in the majority of human cancers.…”

Section: Uiccmentioning

confidence: 99%

Ascochlorin activates p53 in a manner distinct from DNA damaging agents

Jeong

Nakajima

Magae

et al. 2009

Intl Journal of Cancer

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Ascochlorin, a prenylphenol antitumor antibiotic, profoundly increases the expression of endogenous p53 by increasing protein stability in the human osteosarcoma cells and human colon cancer cells. Ascochlorin also increases DNA binding activity to the p53 consensus sequence in nuclear extract and enhances transcription of p53 downstream targets. Ascochlorin specifically induces p53 phosphorylation at ser 392 without affecting ser 15 or 20, whereas DNA damaging agents typically phosphorylate these serines. Moreover, ascochlorin does not induce phosphorylation of ATM and CHK1, an established substrate of ATR that is activated by genotoxins, nor does it increase DNA strand break, as confirmed by comet assay. The structure-activity relationship suggests that p53 activation by ascochlorin is related to inhibition of mitochondrial respiration, which is further supported by the observation that respiratory inhibitors activate p53 in a manner similar to ascochlorin. These results suggest that ascochlorin, through the inhibition of mitochondrial respiration, activates p53 through a mechanism distinct from genotoxins. ' UICCKey words: AP-1; p53; mitochondrial respiration; ascochlorin; ATM; ATR Ascochlorin and ascofuranone ( Fig. 1) are prenylphenol antifungal antibiotics isolated from an incomplete fungus, Ascochyta viciae. Although originally reported to be an antiviral antibiotic, 1-3 ascochlorin and its derivatives exhibit a large variety of physiological activities including hypolipidemic activity, 2 suppression of hypertension, 4 amelioration of types I and II diabetes, 5,6 immunomodulation 7 and antitumor activity. 8,9 Ascochlorin and ascofuranone, one of its derivatives, inhibit oxidative phosphorylation by hindering ubiquinone-dependent electron transport in isolated mitochondria, 10-12 and it has been suggested that the antiviral activity of ascochlorin and macrophage activation by ascofuranone are a result of this inhibitory activity on mitochondrial respiration. 10,11,13 These compounds also modulate the activity of nuclear hormone receptors, 14 which suggests that mechanisms other than those involving the respiratory chain contribute to their physiological activities.Ascochlorin-related compounds show profound antitumor activity against a variety of transplantable tumors and suppress the metastasis of melanomas and lung carcinomas in murine animal models. 8,9 Because pretreatment with ascofuranone before tumor implantation is as effective as treatment after tumor implantation, the antitumor activity of ascofuranone must be mediated, at least in part, by activation of a host defense mechanism against tumors. We recently found that ascochlorin and ascofuranone selectively suppress the AP-1 activity of human renal carcinoma cells, as well as its downstream targets such as matrix metalloproteinase-9, through suppression of the Erk1/2 signaling pathway, 15,16 suggesting that ascochlorin directly suppresses tumor malignancy by this mechanism. We also found that human breast cancer cell lines that are devoid of es...

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Aberrant Expression of Fra-1 in Estrogen Receptor-negative Breast Cancers and Suppression of their Propagation In Vivo by Ascochlorin, an Antibiotic that Inhibits Cellular Activator Protein-1 Activity

Cited by 20 publications

References 41 publications

Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties

Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties

4-O-Carboxymethyl Ascochlorin Causes ER Stress and Induced Autophagy in Human Hepatocellular Carcinoma Cells

Ascochlorin activates p53 in a manner distinct from DNA damaging agents

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