The Experts below are selected from a list of 123 Experts worldwide ranked by ideXlab platform
Tsuyoshi Akiyoshi - One of the best experts on this subject based on the ideXlab platform.
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lymphokine activated Killer Cell function of peripheral blood mononuclear Cells spleen Cells and regional lymph node Cells in gastric cancer patients
Clinical and Experimental Immunology, 2008Co-Authors: Nobuya Karimine, Shigeru Nanbara, Shinya Arinaga, Hiroaki Ueo, H Inoue, Tsuyoshi AkiyoshiAbstract:Lymphokine-Activated Killer (LAK) Cells generated by culture of peripheral blood mononuclear Cells (PBMC), spleen Cells (SPC) and regional lymph node Cells (LNC) with IL-2 for 4 days were examined for their functional capabilities in 29 patients with gastric carcinoma. The cytotoxic activity of LAK Cells induced from LNC was significantly lower than that from either PBMC or SPC, although there was no difference between PBMC or SPC. The induction of mRNA of interferon-gamma (IFN-gamma) or tumour necrosis factor-alpha (TNF-alpha) and the production of these cytokines in the non-adherent LAK Cells from LNC were also significantly reduced compared with those from PBMC or SPC. Further, the LAK Cells from LNC secreted significantly lower levels of these cytokines when stimulated with tumour target, Raji Cells, although the production of these cytokines was markedly increased by stimulation with the targets in all three Cell populations. Phenotypic analysis of each Cell population revealed a decreased proportion of the Cells mediating natural Killer (NK) activity, including CD16+, CD56+, and CD57+ Cells in LNC either before or after culture, although OKIa1+ and CD25+ Cells were uniformly increased in all Cell populations after culture. Changes in subpopulations of CD4+ and CD8+ Cells in LNC were not apparently different from PBMC or SPC. These results indicated the differential reactivity of each lymphocyte population to IL-2 and the reduced LAK Cell function of LNC compared with PBMC or SPC in patients with gastric carcinoma.
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lymphokine activated Killer Cell activity of peripheral blood spleen regional lymph node and tumor infiltrating lymphocytes in gastric cancer patients
Journal of Surgical Oncology, 1994Co-Authors: Nobuya Karimine, Shigeru Nanbara, Shinya Arinaga, Tsukasa Asoh, Hiroaki Ueo, Tsuyoshi AkiyoshiAbstract:Lymphokine-Activated Killer (LAK) Cell activity of peripheral blood mononuclear Cells (PBM), spleen Cells (SPC), regional lymph node Cells (LNC), and tumor-infiltrating lymphocytes (TIL), induced by activation with interleukin 2 (IL 2) for 4 days, was evaluated in patients with gastric carcinoma. TIL exhibited the lowest LAK activity and the cytotoxicity of LNC was significantly lower than that of either PBM or SPC. There was no difference between PBM and SPC. Then, there were significant correlations of LAK activity among PBM, SPC, and LNC, whereas poor correlations were observed in the cytotoxicity between TIL and PBM, SPC, or LNC. Phenotypic analysis of each Cell population was performed before and after activation with IL 2. Before culture, the Cells mediating natural Killer (NK) activity such as CD16+, CD56+, and CD57+ Cells were few in LNC and TIL. However, CD56+ and CD57+ Cells in TIL were increased after culture. Then, CD4+Leu8+ and CD8+CD11+ Cells, which identify suppressor Cell function, were not elevated in LNC or TIL, as compared to that in PBM or SPC. Further, the proportions of OKIa1+ and CD25+ Cells expressing T-Cell activation and IL 2 receptor were uniformly increased in all Cell populations after culture. These results indicate the differential reactivity of each lymphocyte population to IL 2 and fundamental dysfunction of LNC and, especially TIL, suggesting the specific influence of the local tumor environment on the lymphocyte function in the area in patients with gastric carcinoma.
Zigang Dong - One of the best experts on this subject based on the ideXlab platform.
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acetylshikonin suppressed growth of colorectal tumour tissue and Cells by inhibiting the intraCellular kinase t lymphokine activated Killer Cell originated protein kinase
British Journal of Pharmacology, 2020Co-Authors: Ran Zhao, Zigang Dong, Bu Young Choi, Lixiao Wei, Mangaladoss Fredimoses, Fanxiang Yin, Hanyong Chen, Kangdong Liu, Joydeb Kumar Kundu, Meehyun LeeAbstract:Background and purpose Overexpression or aberrant activation of the T-Lymphokine-Activated Killer Cell-originated protein kinase (TOPK) promotes gene expression and growth of solid tumours, implying that TOPK would be a rational target in developing novel anticancer drugs. Acetylshikonin, a diterpenoid compound isolated from Lithospermum erythrorhizon root, exerts a range of biological activities. Here we have investigated whether acetylshikonin, by acting as an inhibitor of TOPK, can attenuate the proliferation of colorectal cancer Cells and the growth of patient-derived tumours, in vitro and in vivo. Experimental approach Targets of acetylshikonin, were identified using kinase profiling analysis, kinetic/binding assay, and computational docking analysis and knock-down techniques. Effects of acetylshikonin on colorectal cancer growth and the underlying mechanisms were evaluated in Cell proliferation assays, propidium iodide and annexin-V staining analyses and western blots. Patient-derived tumour xenografts in mice (PDX) and immunohistochemistry were used to assess anti-tumour effects of acetylshikonin. Key results Acetylshikonin directly inhibited TOPK activity, interacting with the ATP-binding pocket of TOPK. Acetylshikonin suppressed Cell proliferation by inducing Cell cycle arrest at the G1 phase, stimulated apoptosis, and increased the expression of apoptotic biomarkers in colorectal cancer Cell lines. Mechanistically, acetylshikonin diminished the phosphorylation and activation of TOPK signalling. Furthermore, acetylshikonin decreased the volume of PDX tumours and reduced the expression of TOPK signalling pathway in xenograft tumours. Conclusion and implications Acetylshikonin suppressed growth of colorectal cancer Cells by attenuating TOPK signalling. Targeted inhibition of TOPK by acetylshikonin might be a promising new approach to the treatment of colorectal cancer.
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requirement of t lymphokine activated Killer Cell originated protein kinase for trail resistance of human hela cervical cancer Cells
Biochemical and Biophysical Research Communications, 2010Co-Authors: Hyeok Ran Kwon, Ki Won Lee, Zigang Dong, Kyung Bok LeeAbstract:T-Lymphokine-Activated Killer Cell-originated protein kinase (TOPK) appears to be highly expressed in various cancer Cells and to play an important role in maintaining proliferation of cancer Cells. However, the underlying mechanism by which TOPK regulates growth of cancer Cells remains elusive. Here we report that upregulated endogenous TOPK augments resistance of cancer Cells to apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand (TRAIL). Stable knocking down of TOPK markedly increased TRAIL-mediated apoptosis of human HeLa cervical cancer Cells, as compared with control Cells. Caspase 8 or caspase 3 activities in response to TRAIL were greatly incremented in TOPK-depleted Cells. Ablation of TOPK negatively regulated TRAIL-mediated NF-κB activity. Furthermore, expression of NF-κB-dependent genes, FLICE-inhibitory protein (FLIP), inhibitor of apoptosis protein 1 (c-IAP1), or X-linked inhibitor of apoptosis protein (XIAP) was reduced in TOPK-depleted Cells. Collectively, these findings demonstrated that TOPK contributed to TRAIL resistance of cancer Cells via NF-κB activity, suggesting that TOPK might be a potential molecular target for successful cancer therapy using TRAIL.
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t lymphokine activated Killer Cell originated protein kinase functions as a positive regulator of c jun nh2 kinase 1 signaling and h ras induced Cell transformation
Cancer Research, 2007Co-Authors: Feng Zhu, Ki Won Lee, Yongyeon Cho, Bong Seok Kang, Honggyum Kim, Tatyana A Zykova, Ann M Bode, Zigang DongAbstract:T-lymphokine–activated Killer Cell–originated protein kinase (TOPK) is overexpressed in highly proliferating tumors such as leukemias and myelomas, and seems to play a key role in tumorigenesis or metastasis. However, the precise role and regulatory mechanism explaining the effects of TOPK on tumor Cells still remain elusive. Here, we reported that TOPK regulates UVB-induced c-Jun-NH 2 -kinase 1 (JNK1) activity, and is essential for H-Ras–induced activator protein-1 activity and Cell transformation. We showed that TOPK associated with and phosphorylated JNK1 following UVB irradiation in vitro or in vivo . Moreover, UVB-induced JNK1 activity was greatly augmented in mouse epidermal JB6 Cl41 Cells that stably expressed TOPK cDNA. On the other hand, JNK1 activity was markedly attenuated by stable expression of small interfering RNA against TOPK in malignant melanoma RPMI 7951 Cells. Interestingly, TOPK interacted with JNK-interacting protein 1 and caused an elevation of JNK-interacting protein 1 scaffolding activity, thereby enhancing JNK1 activity. Furthermore, JNK1 was required for TOPK-mediated activator protein-1 transcriptional activity and transformed foci induced by UVB or H-Ras. Taken together, these findings showed that TOPK positively modulated UVB-induced JNK1 activity and played a pivotal role in JNK1-mediated Cell transformation induced by H-Ras. These studies might also provide a novel molecular mechanism for the role of TOPK in UVB-mediated skin carcinogenesis. [Cancer Res 2007;67(11):5186–94]
Nobuya Karimine - One of the best experts on this subject based on the ideXlab platform.
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lymphokine activated Killer Cell function of peripheral blood mononuclear Cells spleen Cells and regional lymph node Cells in gastric cancer patients
Clinical and Experimental Immunology, 2008Co-Authors: Nobuya Karimine, Shigeru Nanbara, Shinya Arinaga, Hiroaki Ueo, H Inoue, Tsuyoshi AkiyoshiAbstract:Lymphokine-Activated Killer (LAK) Cells generated by culture of peripheral blood mononuclear Cells (PBMC), spleen Cells (SPC) and regional lymph node Cells (LNC) with IL-2 for 4 days were examined for their functional capabilities in 29 patients with gastric carcinoma. The cytotoxic activity of LAK Cells induced from LNC was significantly lower than that from either PBMC or SPC, although there was no difference between PBMC or SPC. The induction of mRNA of interferon-gamma (IFN-gamma) or tumour necrosis factor-alpha (TNF-alpha) and the production of these cytokines in the non-adherent LAK Cells from LNC were also significantly reduced compared with those from PBMC or SPC. Further, the LAK Cells from LNC secreted significantly lower levels of these cytokines when stimulated with tumour target, Raji Cells, although the production of these cytokines was markedly increased by stimulation with the targets in all three Cell populations. Phenotypic analysis of each Cell population revealed a decreased proportion of the Cells mediating natural Killer (NK) activity, including CD16+, CD56+, and CD57+ Cells in LNC either before or after culture, although OKIa1+ and CD25+ Cells were uniformly increased in all Cell populations after culture. Changes in subpopulations of CD4+ and CD8+ Cells in LNC were not apparently different from PBMC or SPC. These results indicated the differential reactivity of each lymphocyte population to IL-2 and the reduced LAK Cell function of LNC compared with PBMC or SPC in patients with gastric carcinoma.
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lymphokine activated Killer Cell activity of peripheral blood spleen regional lymph node and tumor infiltrating lymphocytes in gastric cancer patients
Journal of Surgical Oncology, 1994Co-Authors: Nobuya Karimine, Shigeru Nanbara, Shinya Arinaga, Tsukasa Asoh, Hiroaki Ueo, Tsuyoshi AkiyoshiAbstract:Lymphokine-Activated Killer (LAK) Cell activity of peripheral blood mononuclear Cells (PBM), spleen Cells (SPC), regional lymph node Cells (LNC), and tumor-infiltrating lymphocytes (TIL), induced by activation with interleukin 2 (IL 2) for 4 days, was evaluated in patients with gastric carcinoma. TIL exhibited the lowest LAK activity and the cytotoxicity of LNC was significantly lower than that of either PBM or SPC. There was no difference between PBM and SPC. Then, there were significant correlations of LAK activity among PBM, SPC, and LNC, whereas poor correlations were observed in the cytotoxicity between TIL and PBM, SPC, or LNC. Phenotypic analysis of each Cell population was performed before and after activation with IL 2. Before culture, the Cells mediating natural Killer (NK) activity such as CD16+, CD56+, and CD57+ Cells were few in LNC and TIL. However, CD56+ and CD57+ Cells in TIL were increased after culture. Then, CD4+Leu8+ and CD8+CD11+ Cells, which identify suppressor Cell function, were not elevated in LNC or TIL, as compared to that in PBM or SPC. Further, the proportions of OKIa1+ and CD25+ Cells expressing T-Cell activation and IL 2 receptor were uniformly increased in all Cell populations after culture. These results indicate the differential reactivity of each lymphocyte population to IL 2 and fundamental dysfunction of LNC and, especially TIL, suggesting the specific influence of the local tumor environment on the lymphocyte function in the area in patients with gastric carcinoma.
Yusuke Nakamura - One of the best experts on this subject based on the ideXlab platform.
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topk t lak Cell originated protein kinase inhibitor exhibits growth suppressive effect on small Cell lung cancer
Cancer Science, 2017Co-Authors: Jaehyun Park, Hiroyuki Inoue, Taigo Kato, Makda Zewde, Takashi Miyamoto, Yo Matsuo, Ravi Salgia, Yusuke NakamuraAbstract:T-Lymphokine-Activated Killer Cell-originated protein kinase (TOPK) plays critical roles in cancer Cell proliferation as well as maintenance of cancer stem Cells (CSC). Small Cell lung cancer (SCLC) has highly aggressive phenotype, reveals early spread to distant sites, and results in dismal prognosis with little effective treatment. In this study, we demonstrate that TOPK expression was highly upregulated in both SCLC Cell lines and primary tumors. Similar to siRNA-mediated TOPK knockdown effects, treatment with a potent TOPK inhibitor, OTS514, effectively suppressed growth of SCLC Cell lines (IC50 ; 0.4-42.6 nM) and led to their apoptotic Cell death. TOPK inhibition caused Cell morphologic changes in SCLC Cells, elongation of interCellular bridges caused by cytokinesis defects or neuronal protrusions induced by neuronal differentiation in a subset of CSC-like SCLC Cells. Treatment with OTS514 suppressed forkhead box protein M1 (FOXM1) activity, which was involved in stemness of CSC. Furthermore, OTS514 treatment reduced CD90-positive SCLC Cells and showed higher cytotoxic effect against lung sphere-derived CSC-like SCLC Cells. Collectively, our results suggest that targeting TOPK is a promising approach for SCLC therapy.
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topk inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis
Science Translational Medicine, 2014Co-Authors: Yo Matsuo, Jaehyun Park, Takashi Miyamoto, Shinji Yamamoto, Shoji Hisada, Houda Alachkar, Yusuke NakamuraAbstract:TOPK (T-Lymphokine-Activated Killer Cell-originated protein kinase) is highly and frequently transactivated in various cancer tissues, including lung and triple-negative breast cancers, and plays an indispensable role in the mitosis of cancer Cells. We report the development of a potent TOPK inhibitor, OTS964 {(R)-9-(4-(1-(dimethylamino)propan-2-yl)phenyl)-8-hydroxy-6-methylthieno[2,3-c]quinolin-4(5H)-one}, which inhibits TOPK kinase activity with high affinity and selectivity. Similar to the knockdown effect of TOPK small interfering RNAs (siRNAs), this inhibitor causes a cytokinesis defect and the subsequent apoptosis of cancer Cells in vitro as well as in xenograft models of human lung cancer. Although administration of the free compound induced hematopoietic adverse reactions (leukocytopenia associated with thrombocytosis), the drug delivered in a liposomal formulation effectively caused complete regression of transplanted tumors without showing any adverse reactions in mice. Our results suggest that the inhibition of TOPK activity may be a viable therapeutic option for the treatment of various human cancers.
Michael T Lotze - One of the best experts on this subject based on the ideXlab platform.
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a tumor Cell selective inhibitor of mitogen activated protein kinase phosphatases sensitizes breast cancer Cells to lymphokine activated Killer Cell activity
Journal of Pharmacology and Experimental Therapeutics, 2017Co-Authors: Christof Kaltenmeier, Laura L Vollmer, Lawrence Vernetti, Lindsay Caprio, Keanu Davis, Vasiliy N Korotchenko, Billy W Day, Michael Tsang, Keren I Hulkower, Michael T LotzeAbstract:Dual specificity mitogen-activated protein kinase (MAPK) phosphatases [dual specificity phosphatase/MAP kinase phosphatase (DUSP-MKP)] have been hypothesized to maintain cancer Cell survival by buffering excessive MAPK signaling caused by upstream activating oncogenic products. A large and diverse body of literature suggests that genetic depletion of DUSP-MKPs can reduce tumorigenicity, suggesting that hyperactivating MAPK signaling by DUSP-MKP inhibitors could be a novel strategy to selectively affect the transformed phenotype. Through in vivo structure-activity relationship studies in transgenic zebrafish we recently identified a hyperactivator of fibroblast growth factor signaling [(E)-2-benzylidene-5-bromo-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI-215)] that is devoid of developmental toxicity and restores defective MAPK activity caused by overexpression of DUSP1 and DUSP6 in mammalian Cells. Here, we hypothesized that BCI-215 could selectively affect survival of transformed Cells. In MDA-MB-231 human breast cancer Cells, BCI-215 inhibited Cell motility, caused apoptosis but not primary necrosis, and sensitized Cells to Lymphokine-Activated Killer Cell activity. Mechanistically, BCI-215 induced rapid and sustained phosphorylation of extraCellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) in the absence of reactive oxygen species, and its toxicity was partially rescued by inhibition of p38 but not JNK or ERK. BCI-215 also hyperactivated MKK4/SEK1, suggesting activation of stress responses. Kinase phosphorylation profiling documented BCI-215 selectively activated MAPKs and their downstream substrates, but not receptor tyrosine kinases, SRC family kinases, AKT, mTOR, or DNA damage pathways. Our findings support the hypothesis that BCI-215 causes selective cancer Cell cytotoxicity in part through non-redox-mediated activation of MAPK signaling, and the findings also identify an intersection with immune Cell killing that is worthy of further exploration.
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high mobility group box i hmgb1 release from tumor Cells after treatment implications for development of targeted chemoimmunotherapy
Journal of Immunotherapy, 2007Co-Authors: Xiang Da Eric Dong, Michael T Lotze, Norimasa Ito, Richard A Demarco, Petar J Popovic, Stuart H Shand, Simon C Watkins, S Winikoff, Charles K Brown, David L BartlettAbstract:We have recently demonstrated that cytolysis of human melanoma Cells by immune effectors (both NK and T Cells) is associated with release of the nuclear chromatin protein, high mobility group box I (HMGB1). ExtraCellular HMGB1 mediates a number of important functions including endothelial Cell activation, stromagenesis, recruitment and activation of innate immune Cells, and also dendritic Cell maturation that, in the setting of cancer, lead to a chronic inflammatory response. This reparative inflammatory response promotes tumor Cell survival, expansion, and metastases. Release of HMGB1 after chemotherapy-induced cytotoxicity has not been well characterized. We measured the release of HMGB1 after chemotherapy or immune cytolysis and demonstrated that this did not correlate with conventional markers of apoptosis and necrosis in several human colorectal, pancreatic, and melanoma tumor Cell lines. Rather, we observed that tumor Cells incubated with the platinating agent oxaliplatin, retained HMGB1 within the nucleus for significantly longer periods than other agents used at comparable cytotoxic concentrations or even with potent cytolytic Cells. Thus, release of HMGB1 from dying tumor Cells treated with chemotherapy or Cells with lymphokine activated Killer Cell activity is not dependent solely on the mode of Cell death. Sequestration of the damage associated molecular pattern molecule, HMGB1, may play a role in the clinical efficacy of platinating agents and suggests this as a superior agent for coupling with immunotherapeutic strategies, possibly enhancing their effectiveness.
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systemic administration of Cellular il 10 induces an effective specific and long lived immune response against established tumors in mice
Journal of Immunology, 1996Co-Authors: R M Berman, Tadamichi Suzuki, Hideaki Tahara, Paul D Robbins, Satwant K Narula, Michael T LotzeAbstract:Cellular IL-10 (cIL-10), the collective term for human and murine IL-10, has both stimulatory and inhibitory effects on diverse Cell types, including costimulation of T Cell proliferation, chemoattraction of CD8+ T Cells, and stimulation of Lymphokine-Activated Killer Cell activity. Human IL-10 (hIL-10) differs from its EBV homolog viral IL-10 (vIL-10) by only 16% at the amino acid level; however, vIL-10 shares with cIL-10 predominantly inhibitory effects, such as macrophage deactivation. We administered cIL-10 systemically to mice bearing established (day 7) sarcomas, melanomas, or colorectal carcinomas. At high doses (20 to 60 micrograms/day x 7 days), cIL-10 induced rejection of tumors, delaying tumor outgrowth or resulting in complete cure. Sublethal irradiation (500 rad) of mice prior to tumor inoculation abrogated the IL-10 effect. Cured mice were immune to subsequent rechallenge with 10-fold higher inoculation with the same, but not a different, tumor. IL-12 also has potent antitumor activity and interacts with IL-10 in both complementary and antagonistic ways; co-administration of both cytokines resulted in additive antitumor activity. To compare cIL-10 vs vIL-10 effects in vivo, we engineered CL8-1 melanoma transfectants bearing the vIL-10 or the murine IL-10 (mIL-10) gene. Local secretion of mIL-10 induced rejection of tumors, while vIL-10 resulted in accelerated outgrowth. Subsequent systemic administration of cIL-10 to mice bearing vIL-10-transduced tumors completely reversed the local suppressive effects, leading to rejection, suggesting distinct pathways for cIL-10 and vIL-10 effects. That cIL-10 can stimulate the acquisition of an effective, specific, and long-lived antitumor immune response in murine models and can reverse the local immunosuppressive effects of vIL-10 indicates a potential role for cIL-10 administration in the biologic therapy of cancer and suggests a broader interpretation of IL-10 biology.
