Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells

Thaler, Roman; Spitzer, Silvia; Karlic, Heidrun; Berger, Christian E.; Klaushofer, Klaus; Varga, Franz

doi:10.1016/j.bcp.2012.10.016

Cited by 22 publications

(15 citation statements)

References 81 publications

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“…The results of this work show that SFN, besides possible effects on DNA demethylation patterns from ascorbic acid occurring in the culture medium (65), promotes Tet-mediated hydroxymethylation, which is a key mechanistic step in the derepression of gene transcription silenced by CpG methylation, and demethylation of FAS promoter frequently activates the expression of this gene as shown in tumor treatment (66). Because loss of CpG methylation decreases the gene-repressive histone mark H3K27me3 (67), SFN may indirectly increase formation of transcriptionally active acetylated histones H3 and H4.…”

Section: Discussionmentioning

confidence: 97%

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Thaler

Maurizi

Roschger

et al. 2016

Journal of Biological Chemistry

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Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation via Tet1 and Tet2 and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2, Col1a1, Bglap2, Sp7, Atf4, and Alpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-B ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of the Tet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (ϳ20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorption in vivo. Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis.

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Section: Discussionmentioning

confidence: 97%

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Thaler

Maurizi

Roschger

et al. 2016

Journal of Biological Chemistry

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“…After incubation, 100 μL of caspase 3/7 reagent containing buffer and substrate were added to each well, mixed and incubated for 1 h at room temperature in the dark. Luminescence was measured with the multi‐label reader Victor X5 (Perkin Elmer; Waltham, MA) and caspase activity was expressed in relative light units (RLU) . Luminescence was normalized to cell titer using a CellTiter‐Glo® Luminescent Cell Viability Assay (Promega).…”

Section: Methodsmentioning

confidence: 99%

ROS signaling by NADPH oxidase 5 modulates the proliferation and survival of prostate carcinoma cells

Höll

Kozieł

Schäfer

et al. 2015

Molecular Carcinogenesis

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Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of male cancer death in Western nations. Thus, new treatment modalities are urgently needed. Elevated production of reactive oxygen species (ROS) by NADPH oxidase (Nox) enzymes is implicated in tumorigenesis of the prostate and other tissues. However, the identity of the Nox enzyme(s) involved in prostate carcinogenesis remains largely unknown. Analysis of radical prostatectomy tissue samples and benign and malignant prostate epithelial cell lines identified Nox5 as an abundantly expressed Nox isoform. Consistently, immunohistochemical staining of a human PCa tissue microarray revealed distinct Nox5 expression in epithelial cells of benign and malignant prostatic glands. shRNA‐mediated knockdown of Nox5 impaired proliferation of Nox5‐expressing (PC‐3, LNCaP) but not Nox5‐negative (DU145) PCa cell lines. Similar effects were observed upon ROS ablation via the antioxidant N‐acetylcysteine confirming ROS as the mediators. In addition, Nox5 silencing increased apoptosis of PC‐3 cells. Concomitantly, protein kinase C zeta (PKCζ) protein levels and c‐Jun N‐terminal kinase (JNK) phosphorylation were reduced. Moreover, the effect of Nox5 knockdown on PC‐3 cell proliferation could be mimicked by pharmacological inhibition of JNK. Collectively, these data indicate that Nox5 is expressed at functionally relevant levels in the human prostate and clinical PCa. Moreover, findings herein suggest that Nox5‐derived ROS and subsequent depletion of PKCζ and JNK inactivation play a critical role in modulating intracellular signaling cascades involved in the proliferation and survival of PCa cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

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“…155–159 Treatment of osteosarcoma cells with ibandronate was shown to inhibit activated Ras and downregulate DNMT expression, resulting in increased levels of Fas expression in vitro . 160 …”

Section: Epigeneticsmentioning

confidence: 99%

Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies

2015

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Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Unfortunately, clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. This stagnation in therapeutic advances is perhaps explained by the genetic, epigenetic, and biological complexities of this rare tumor. In this review we provide a general background on the biology of osteosarcoma and the clinical status quo. We go on to enumerate the genetic and epigenetic defects identified in osteosarcoma. Finally, we discuss ongoing large-scale studies in the field and potential new therapies that are currently under investigation.

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Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells

Abstract: Graphical abstract

Cited by 22 publications

References 81 publications

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

ROS signaling by NADPH oxidase 5 modulates the proliferation and survival of prostate carcinoma cells

Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies

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