Mechanisms of Tumor Growth Inhibition by Depletion of γ-Glutamylcyclotransferase (GGCT): A Novel Molecular Target for Anticancer Therapy.

γ-Glutamylcyclotransferase (GGCT), which is one of the major enzymes involved in glutathione metabolism, is upregulated in a wide range of cancers-glioma, breast, lung, esophageal, gastric, colorectal, urinary bladder, prostate, cervical, ovarian cancers and osteosarcoma-and promotes cancer progression; its depletion leads to the suppression of proliferation, invasion, and migration of cancer cells. It has been demonstrated that the suppression or inhibition of GGCT has an antitumor effect in cancer-bearing xenograft mice. Based on these observations, GGCT is now recognized as a promising therapeutic target in various cancers.

Depletion of gamma-glutamylcyclotransferase in cancer cells induces autophagy followed by cellular senescence.

Gamma-glutamylcyclotransferase (GGCT) was originally identified as a protein highly expressed in bladder cancer tissues by proteomic analysis, and its higher expression in a variety of cancers compared to normal tissues have been shown. Depletion of GGCT in various cancer cells results in antiproliferative effects both and ; thus it is considered a promising therapeutic target. Although it has been shown that knockdown of GGCT induces cellular senescence and non-apoptotic cell death, associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs) including p21, the cellular events that follow GGCT depletion are not fully understood.

A Novel Prodrug of a γ-Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer.

γ-Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester-type cell-permeable prodrug, pro-GA, was developed based on the structure of N-glutaryl-l-alanine (GA), by structure optimization using temporary fluorophore-tagged prodrug candidates.

Prohibitin-2 is a novel regulator of p21 induced by depletion of γ-glutamylcyclotransferase.

Previous studies show that gamma-glutamylcyclotransferase (GGCT) is expressed at high levels in various cancer tissues and that its knockdown inhibits MCF7 cancer cell growth via upregulation of p21 (p21). However, the detailed underlying mechanism is unclear. Here, we used yeast two-hybrid screening and co-immunoprecipitation to identify Prohibitin-2 (PHB2) as a novel protein that interacts with GGCT.

Depletion of γ-glutamylcyclotransferase inhibits breast cancer cell growth via cellular senescence induction mediated by CDK inhibitor upregulation.

Background: Chromosome 7 open reading frame 24 (C7orf24) was originally identified as a highly expressed protein in various types of cancer, and later shown to be a γ-glutamylcyclotransferase (GGCT). GGCT depletion in cancer cells has anti-proliferative effects in vitro and in vivo, and it is therefore considered a promising candidate as a therapeutic target. However, the cellular events induced by GGCT depletion remain unclear.

Synthesis and GGCT Inhibitory Activity of N-Glutaryl-L-alanine Analogues.

γ-Glutamylcyclotransferase (GGCT) is an important enzyme that cleaves γ-glutamyl-amino acid in the γ-glutamyl cycle to release 5-oxoproline and amino acid. Eighteen N-acyl-L-alanine analogues including eleven new compounds have been synthesized and examined for their inhibitory activity against recombinant human GGCT protein. Simple N-glutaryl-L-alanine was found to be the most potent inhibitor for GGCT.

Temperature and zooplankton size structure: climate control and basin-scale comparison in the North Pacific.

The global distribution of zooplankton community structure is known to follow latitudinal temperature gradients: larger species in cooler, higher latitudinal regions. However, interspecific relationships between temperature and size in zooplankton communities have not been fully examined in terms of temporal variation. To re-examine the relationship on a temporal scale and the effects of climate control thereon, we investigated the variation in copepod size structure in the eastern and western subarctic North Pacific in 2000-2011.

A GGCT fluorogenic probe: design, synthesis and application to cancer-related cells.

Cancer-related γ-glutamyl cyclotransferase (GGCT) specifically converts γ-glutamyl amino acids (γ-Glu-Xaa) into pyroglutamate and the corresponding amino acids (Xaa). Here we report a novel GGCT fluorogenic probe "LISA-101" containing a masked O-acylated fluorophore "resorufin" on the side chain of the P amino acid (Xaa). Upon GGCT treatment, the P amino acid was liberated and spontaneously released the intact fluorophore.

Establishment of a vascular endothelial cell-reactive type II NKT cell clone from a rat model of autoimmune vasculitis.

We previously generated a rat model that spontaneously developed small vessel vasculitis (SVV). In this study, a T cell clone reactive with rat vascular endothelial cells (REC) was established and named VASC-1. Intravenous injection of VASC-1 induced SVV in normal recipients.

A fluorogenic probe for γ-glutamyl cyclotransferase: application of an enzyme-triggered O-to-N acyl migration-type reaction.

Light it up: human chromosome 7 ORF 24, a tumor-related protein, has been identified as a γ-glutamyl cyclotransferase (GGCT) in the glutathione homeostasis cycle. The singular substrate preference of the enzyme has hampered chemical probe development, and no fluorogenic probe has been reported. Here we report the first fluorogenic dipeptide probe, LISA-4, which should contribute toward further understanding of GGCT.

Synchronized Babinski and Chaddock signs preceded the MRI findings in a case of repetitive transient ischemic attack.

We herein report a 53-year-old female with repeated transient ischemic attack (TIA) symptoms including 13 instances of right hemiparesis that decreased in duration over 4 days. Two separate examinations using diffusion weighted image (DWI) in magnetic resonance imaging (MRI) revealed normal findings, but we observed that both Babinski and Chaddock signs were completely synchronized with her right hemiparesis. We were only able to diagnose this case of early stage TIA using clinical signs.

Association of epigenetic alterations in the human C7orf24 gene with the aberrant gene expression in malignant cells.

Human chromosome 7 open reading frame 24 (C7orf24)/γ-glutamyl cyclotransferase has been suggested to be a potential diagnostic marker for several cancers, including carcinomas in the bladder urothelium, breast and endometrial epithelium. We here investigated the epigenetic regulation of the human C7orf24 promoter in normal diploid ARPE-19 and IMR-90 cells and in the MCF-7 and HeLa cancer cell lines to understand the transcriptional basis for the malignant-associated high expression of C7orf24. Chromatin immunoprecipitation analysis revealed that histone modifications associated with active chromatin were enriched in the proximal region but not in the distal region of the C7orf24 promoter in HeLa and MCF-7 cells.

Prediction of response to treatment by gene expression profiling of peripheral blood in patients with microscopic polyangiitis.

The JMAAV study was an open-labeled prospective clinical trial, which proposed severity-based treatment protocols for patients with microscopic polyangiitis (MPA). The results suggest that the proposed protocols are useful (remission rate: 89.4%), but are also indicative of relapse or patient demise regardless of the treatment (recurrence rate: 19.

Prevention of tumor growth by needle-free jet injection of anti-C7orf24 siRNA.

Chromosome 7 open reading frame 24 (C7orf24), which was identified by proteome analysis, is upregulated in various types of cancer and is associated with cellular proliferation. However, in vivo antitumor effect by knockdown of C7orf24 has not been clarified. In this study, we investigated that the antitumor effect of anti-C7orf24 small interfering RNA (siRNA) administered by needle-free jet injection (JI) on lung cancer-bearing mice.

Pathogenesis of Vasculitis in env-pX Rats.

Transgenic rats carrying the env-pX gene of human T-cell leukemia virus type I (env-pX rats) develop necrotizing angiitis resembling human polyarteritis nodosa (PN). In the development of vasculitis in these rats, the thymus plays an important role. In this review, we provide an outline of the pathogenesis of vasculitis observed in env-pX rats, and discuss the developmental mechanism of human necrotizing angiitis such as PN with an unknown cause.

Multiple NF-Y-binding CCAAT boxes are essential for transcriptional regulation of the human C7orf24 gene, a novel tumor-associated gene.

Human chromosome 7 ORF 24 (C7orf24) has been identified as a tumor-related protein, and shown to be a γ-glutamyl cyclotransferase. In the current study, we characterized the promoter region of the human C7orf24 gene to explore the transcriptional regulation of the gene. We revealed that the human C7orf24 promoter is a TATA-less promoter, containing five CCAAT boxes aligned in a forward orientation.

Involvement of cancer biomarker C7orf24 in the growth of human osteosarcoma.

Background: Up-regulation of the expression of the gene C7orf24, encoding γ-glutamyl cyclotransferase, is a common event in cancers derived from various tissues, but its involvement in osteosarcomas (OS) has not yet been demonstrated.

Materials And Methods: The expression of C7orf24 was analyzed in human OS cell lines and primary tumor samples. The biological effects of C7orf24 on growth, motility, and invasion in the OS cell lines were investigated using siRNA for C7orf24.

[Renal arteriovenous fistula induced by blunt renal trauma : a case report].

We report a case of renal arteriovenous fistula (RAVF) following blunt renal trauma. An 84-year-old woman who presented with massive gross hematuria after striking her right flank region on the corner of a table was transferred to neighboring hospital on October 24, 2006. Plain computerized tomography (CT) revealed a small subcapsular hematoma on the right kidney, corresponding to a type I renal injury according to the classification of the Japanese Association for the Surgery of Trauma.

Human endogenous retrovirus-R Env glycoprotein as possible autoantigen in autoimmune disease.

It has long been discussed whether endogenous retroviruses (ERVs) are involved in the pathogenesis of autoimmune diseases. Among various human endogenous retroviruses (HERVs), we have focused on HERV-R. To investigate the biological roles of HERV-R, we earlier established transgenic rats carrying the full sequence of the viral genome.