Kōtō-ku, Japan
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Ohishi T.,Cancer Chemotherapy Center | Hirota T.,Cancer Institute | Tsuruo T.,Cancer Chemotherapy Center | Seimiya H.,Cancer Chemotherapy Center
Cancer Research | Year: 2010

Aurora-A, a conserved serine-threonine kinase, plays essential roles in mitosis. Aberrant upregulation of Aurora-A perturbs proper mitotic progression and results in a generation of multinucleated cells with centrosome amplification. The molecular mechanisms for these mitotic defects remain elusive. Here, we show that the overexpressed Aurora-A-induced mitotic defects depend on the telomeric protein TRF1. Live and fixed cell analyses revealed that Aurora-A overexpression in HeLa cells compromises chromosome biorientation, which leads to cytokinetic failure and tetraploidization with increased centrosome numbers. TRF1 depletion by small interfering RNAs or by tankyrase-1 overexpression suppresses Aurora-A-induced occurrence of unaligned chromosomes in metaphase, thus preventing the subsequent abnormalities. We found that Aurora-A binds and phosphorylates TRF1. When TRF1 knockdown cells are complemented with wild-type TRF1, Aurora-A-induced mitotic defects recur. By contrast, a TRF1 mutant that is not phosphorylatable by Aurora-A does not restore such Aurora-A-induced phenotype. We propose that TRF1 phosphorylation by excessive Aurora-A may provoke abnormal mitosis and chromosomal instability. ©2010 AACR.


Katayama R.,Cancer Chemotherapy Center | Lovly C.M.,Vanderbilt University | Shaw A.T.,Massachusetts General Hospital | Shaw A.T.,Harvard University
Clinical Cancer Research | Year: 2015

The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase was initially discovered as a component of the fusion protein nucleophosmin (NPM)-ALK in anaplastic large-cell lymphoma (ALCL). Genomic alterations in ALK, including rearrangements, point mutations, and genomic amplification, have now been identified in several malignancies, including lymphoma, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, and others. Importantly, ALK serves as a validated therapeutic target in these diseases. Several ALK tyrosine kinase inhibitors (TKI), including crizotinib, ceritinib, and alectinib, have been developed, and some of them have already been approved for clinical use. These ALK inhibitors have all shown remarkable clinical outcomes in ALK-rearranged NSCLC. Unfortunately, as is the case for other kinase inhibitors in clinical use, sensitive tumors inevitably relapse due to acquired resistance. This review focuses on the discovery, function, and therapeutic targeting of ALK, with a particular focus on ALKrearranged NSCLC. © 2015 AACR.


Yoshida M.,Cancer Chemotherapy Center
Proceedings of the Japan Academy Series B: Physical and Biological Sciences | Year: 2010

Molecular biology of mouse and chicken retroviruses had identified oncogenes and provided a revolutionary concept in understanding of cancers. A human retrovirus was established during 1980-1982 in linkage with a unique human leukemia, concurrently in Japan and USA. This review covers our efforts on the discovery of new retrovirus, Human T-cell Leukemia Virus Type 1 (HTLV-1), first introducing to a new class of retroviruses with a unique regulatory factors, Tax and Rex. Then it is followed by analyses of molecular interaction of the vial Tax with cellular machineries involved in the pathogenesis of Adult T-cell Leukemia (ATL). And then a probable mechanism of pathogenesis of ATL is proposed including recent findings on HBZ after our efforts. © 2010 The Japan Academy.


Kong D.,Cancer Chemotherapy Center | Dan S.,Cancer Chemotherapy Center | Yamazaki K.,Cancer Chemotherapy Center | Yamori T.,Cancer Chemotherapy Center
European Journal of Cancer | Year: 2010

As accumulating evidences suggest close involvement of phosphatidylinositol 3-kinase (PI3K) in various diseases particularly cancer, considerable competition occurs in development of PI3K inhibitors. Consequently, novel PI3K inhibitors such as ZSTK474, GDC-0941 and NVP-BEZ235 have been developed. Even though all these inhibitors were reported to inhibit class I PI3K but not dozens of protein kinases, whether they have different molecular targets remained unknown. To investigate such molecular target specificity, we have determined the inhibitory effects of these novel inhibitors together with classical PI3K inhibitor LY294002 on PI3K superfamily (including classes I, II, and III PI3Ks, PI4K and PI3K-related kinases) by using several novel non-radioactive biochemical assays. As a result, ZSTK474 and GDC-0941 indicated highly similar inhibition profiles for PI3K superfamily, with class I PI3K specificity much higher than NVP-BEZ235 and LY294002. We further investigated their growth inhibition effects on JFCR39, a human cancer cell line panel which we established for molecular target identification, and analysed their cell growth inhibition profiles (fingerprints) by using COMPARE analysis programme. Interestingly, we found ZSTK474 exhibited a highly similar fingerprint with GDC-0941 (r = 0.863), more similar than with that of either NVP-BEZ235 or LY294002, suggesting that ZSTK474 shares more in molecular targets with GDC-0941 than with either of the other two PI3K inhibitors, consistent with the biochemical assay result. The biological implication of the difference in molecular target specificity of these PI3K inhibitors is under investigation. © 2010 Elsevier Ltd. All rights reserved.


Hirashima K.,Cancer Chemotherapy Center | Seimiya H.,Cancer Chemotherapy Center
Nucleic Acids Research | Year: 2015

Telomere erosion causes cell mortality, suggesting that longer telomeres enable more cell divisions. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than those of surrounding normal tissues. Recently, we showed that cancer cell telomere elongation represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by elongated telomeres. Here, we report that telomeric repeat-containing RNA (TERRA) induces a genome-wide alteration of gene expression in telomere-elongated cancer cells. Using three different cell lines, we found that telomere elongation up-regulates TERRA signal and down-regulates innate immune genes such as STAT1, ISG15 and OAS3 in vivo. Ectopic TERRA oligonucleotides repressed these genes even in cells with short telomeres under three-dimensional culture conditions. This appeared to occur from the action of G-quadruplexes (G4) in TERRA, because control oligonucleotides had no effect and a nontelomeric G4-forming oligonucleotide phenocopied the TERRA oligonucleotide. Telomere elongation and G4-forming oligonucleotides showed similar gene expression signatures. Most of the commonly suppressed genes were involved in the innate immune system and were up-regulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy by suppressing innate immune genes. © 2015 The Author(s).


Fujita N.,Cancer Chemotherapy Center | Takagi S.,Cancer Chemotherapy Center
Journal of Biochemistry | Year: 2012

Platelets are small blood components that play indispensable roles in the initial stages of coagulation. In addition to their role in haemostasis, platelets participate in inflammation and tissue regeneration under physiological conditions. Recent studies also revealed the role of platelets under pathological conditions, including the oncogenic process. Platelets enhance tumour growth and metastasis by secreting many growth factors and angiogenic factors or by forming a coat around tumour cells in the blood stream. We previously discovered Aggrus (also known as podoplanin, gp36, gp38P, T1alpha and OTS-8) expressed on tumour cell surfaces as a key molecule for tumour-induced platelet aggregation. Aggrus expression is increased in various malignant tumours such as squamous cell carcinomas, mesotheliomas, glioblastomas and osteosarcomas. Detailed analysis revealed that Aggrus contains three tandem repeats of platelet aggregation-stimulating (PLAG) domains that are associated with its platelet aggregation-inducing ability. PLAG domains of Aggrus are involved in binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). Neutralizing monoclonal antibodies that interfere with Aggrus-CLEC-2 binding attenuate Aggrus-induced platelet aggregation, tumour cell growth and metastasis formation. Aggrus is also expressed in advanced atherosclerotic lesions, suggesting that Aggrus is associated with thrombus formation on disrupted atherosclerotic lesions. These data suggest that Aggrus is a promising cell surface target for developing new therapies against cancer and thrombosis. © 2012 The Authors 2012. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.


Saito S.,Cancer Chemotherapy Center | Tomida A.,Cancer Chemotherapy Center
Methods in Enzymology | Year: 2011

Glucose deprivation, one of the major physiological conditions in solid tumor, leads to activation of the unfolded protein response (UPR) in cancer cells. The UPR occurs through the transcriptional and translational regulatory mechanisms that improve the capacity of the endoplasmic reticulum (ER) to fold and traffic proteins and allows the cell to survive under stress conditions. We previously reported that the macrocyclic compound versipelostatin and the antidiabetic biguanides metformin, buformin, and phenformin could inhibit the UPR during glucose deprivation as well as induce the UPR by treatment of cells with 2-deoxy-d-glucose (2DG), a glycolysis inhibitor. Versipelostatin and biguanides show highly selective cytotoxicity to glucose-deprived tumor cells and exert in vivo antitumor activity; thus, these compounds would be interesting anticancer agent candidates. By microarray analysis, we demonstrated that cancer cells under glucose deprivation conditions caused activation of the UPR transcription program, which was suppressed broadly by versipelostatin and biguanides. We also identified the drug-driven gene signatures that can be used to discover pharmacologic UPR modulators. Indeed, we found several bioactive drugs, such as pyrvinium pamoate, valinomycin, and rottlerin, that selectively suppressed 2DG-induced GRP78 promoter activity as versipelostatin and biguanide did. Together with growing bioinformatics databases and analytical tools, our approach could provide a chemical genomic basis for developing UPR-targeting drugs against solid tumors. © 2011 Elsevier Inc.


Kong D.,Tianjin Medical University | Yamori T.,Cancer Chemotherapy Center
Bioorganic and Medicinal Chemistry | Year: 2012

Over the past few decades, panels of human cancer cell lines have made a significant contribution to the discovery and development of anticancer drugs. The National Cancer Institute 60 (NCI60), which consists of 60 cell lines from various human cancer types, remains the most powerful human cancer cell line panel for high throughput screening of anticancer drugs. The development of JFCR39, comprising a panel of 39 human cancer cell lines coupled with a drug-activity database, was based on NCI60. Like NCI60, JFCR39 not only provides disease-oriented information but can also predict the action mechanism or molecular target of a given antitumor agent by utilizing the COMPARE algorithm. The molecular targets of ZSTK474 as well as several other antitumor agents have been identified by using JFCR39 and some of these compounds have since entered clinical trials. In this review, we will describe human cancer cell line panels particularly JFCR39 and its application in the discovery and/or development of anticancer drug candidates. © 2011 Elsevier Ltd. All rights reserved.


Mashima T.,Cancer Chemotherapy Center | Okabe S.,Cancer Chemotherapy Center | Seimiya H.,Cancer Chemotherapy Center
Molecular Pharmacology | Year: 2010

In prostate cancer, blockade of androgen receptor (AR) signaling confers a therapeutic benefit. Nevertheless, this standard therapy allows relapse of hormone-refractory prostate cancer (HRPC) with a poor prognosis. HRPC cells often express variant ARs, such as point-mutated alleles and splicing isoforms, resulting in androgen-independent cell growth and resistance to antiandrogen (e.g., flutamide). However, a pharmacological strategy to block such aberrant ARs remains to be established. Here, we established a reporter system that monitors AR-mediated activation of a prostate-specific antigen (PSA) promoter. Our chemical library screening revealed that the antibiotic nigericin inhibits AR-mediated activation of the PSA promoter and PSA production in prostate cancer cells. Nigericin suppressed the androgen-dependent LNCaP cell growth even though the cells expressed a flutamide-resistant mutant AR. These effects were caused by AR suppression at the mRNA and post-translational levels. In HRPC 22Rv1 cells, which express the full-length AR and the constitutively active, truncated ARs lacking the carboxyl-terminal ligand-binding domain, small interfering RNA-mediated knockdown of both AR isoforms efficiently suppressed the androgen-independent cell growth, whereas knockdown of the full-length AR alone had no significant effect. It is noteworthy that nigericin was able to mimic the knockdown of both AR isoforms: it reduced the expression of the full-length and the truncated ARs, and it induced G1 cell-cycle arrest and apoptosis of 22Rv1 cells. These observations suggest that nigericin-like compounds that suppress AR expression at the mRNA level could be applied as new-type therapeutic agents that inhibit a broad spectrum of AR variants in HRPC. Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics.


Murakami M.,University of Tokyo | Cabral H.,University of Tokyo | Matsumoto Y.,University of Tokyo | Wu S.,University of Tokyo | And 4 more authors.
Science Translational Medicine | Year: 2011

Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.

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