Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells

Shibayama-Imazu, Toshiko; Sonoda, Ikuko; Sakairi, Shizuka; Aiuchi, Toshihiro; Ann, Wei-wei; Nakajo, Shigeo; Itabe, Hiroyuki; Nakaya, Kazuyasu

doi:10.1007/s10495-006-7979-5

Cited by 41 publications

(39 citation statements)

References 37 publications

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“…Because mitochondrial dysfunction is implicated in VK2-induced apoptosis (Shibayama-Imazu et al, 2006), we next examined the effect of VK2 on the mitochondrial-mediated apoptosis pathway. To examine the effect of VK2 on mitochondrial membrane potential, HL60 cells were treated with VK2 or the proton ionophore FCCP, and mitochondrial membrane potential was measured by flow cytometry using Rhodamine 123.…”

Section: Resultsmentioning

confidence: 99%

Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis

et al. 2012

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Vitamin K2 (VK2, menaquinone) is known to have anticancer activity in vitro and in vivo. Although its effect is thought to be mediated, at least in part, by the induction of apoptosis, the underlying molecular mechanism remains elusive. Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis. VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis. Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death. Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak. Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction. Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis. This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis

et al. 2012

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“…We did observe an increase in H 2 O 2 in fresh lysates from Ad-TERE1-infected J82 cells consistent with TERE1-mediated synthesis of vitamins K-2 or K-3. Both vitamin K-2 and K-3 are redox-cycling and alkylating quinones known to generate oxidative stress (superoxide and H 2 O 2 ), alkylate thiols and amines (O'Brien, 1991) and lead to different types of growth inhibition, autoschizis, necrosis, or apoptosis (Lamson and Plaza, 2003;Shibayama-Imazu et al, 2006;Jamison et al, 2010). This also suggests the possibility that TERE1 expression may be an oxidative stress liability that is selected against during tumor cell metabolic reprogramming to the invasive phenotype.…”

Section: Loss Of Tere1 Expression and Bladder Cancer Progressionmentioning

confidence: 99%

“…As a ligand for SXR, vitamin K-2 can activate LXR targets such as APOE and the ABC transporters that efflux vitamin K and cholesterol (Shukla et al, 2007;Chisaki et al, 2009). Pharmacological application of vitamins K-2 and K-3 are also linked to oxidative stress (Gilloteaux et al, 2006;Shibayama-Imazu et al, 2006;Shearer and Newman, 2008;Amalia et al, 2010). APOE is believed to play a role in oxysterol-induced efflux as part of a lipoprotein-mediated defense against oxidative stress (Laffitte et al, 2001;Landes et al, 2003;Carter, 2007;Rezen et al, 2010).…”

Section: Implications Of Tere1 Protein Interactions With Apoementioning

confidence: 99%

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Fredericks

McGarvey

Wang

et al. 2011

DNA and Cell Biology

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Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.

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“…Previous studies have revealed that VK2 are involved not only in Á-carboxylation of proteins but also in the Á-carboxylation independent function, thus suggesting that VK2 possess both Á-carboxylation-dependent and -independent actions (26). As an example of the Á-carboxylationindependent action of VK2, vitamin Ks has been demonstrated to have an anti-proliferative effect in many types of cancer cells including HCC (14,15,18,20,24,(26)(27)(28)(29)(30). In addition to anti-proliferative effects, VK2 also suppresses the invasion of HCC cells (18).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of matrix metalloproteinase expression by menatetrenone, a vitamin K2 analogue

Ide

Zhang²,

Hamajima³

et al. 2009

Oncol Rep

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Abstract. Vitamin K2 (VK2) has been shown to have a potent anti-tumor effect against several cancer types including hepatocellular carcinoma (HCC), but the mechanisms remain to be elucidated. Matrix metalloproteinase (MMP) plays an important role in the invasion and metastasis of cancer cells, but it is not known whether VK2 regulates the expression of MMPs. Human HCC cell lines were treated with VK2 combined with 12-O-tetradecanoyl phorbol-13 acetate (TPA) and the expression of MMPs was examined by reporter gene assay, RT-PCR and Western blotting. VK2 inhibited the basal and TPA-induced expression of MMP-1, -3 and -7 at the transcriptional, mRNA and protein levels in a dosedependent manner. VK2 also inhibited the TPA-induced activation of NF-κB and AP-1 activity. The inhibitors against NF-κB and mitogen-activated protein kinases (MAP kinase) including ERK and JNK pathways suppressed TPA-induced luciferase activity of MMP-1, -3 and -7 promoters. These data suggest that VK2 inhibits MMP expression by suppressing NF-κB and MAP kinase activity and might be potentially useful in the treatment of HCC.

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Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells

Cited by 41 publications

References 37 publications

Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis

Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Inhibition of matrix metalloproteinase expression by menatetrenone, a vitamin K2 analogue

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