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Tumor Cells. (tumor + cells)
Selected AbstractsTranscriptional upregulation of HSP70-2 by HIF-1 in cancer cells in response to hypoxiaINTERNATIONAL JOURNAL OF CANCER, Issue 2 2009Wen-Jie Huang Abstract Heat shock protein 70-2 (HSP70-2) can be expressed by cancer cells and act as an important regulator of cancer cell growth and survival. Here, we show the molecular mechanisms by which hypoxia regulate HSP70-2 expression in cancer cells. When cells were subjected to hypoxia (1% O2), the expression of HSP70-2 had a significant increase in cancer cells. Such increase was due to the direct binding of hypoxia-inducible factor to hypoxia-responsive elements (HREs) in the HSP70-2 promoter. By luciferase assays, we demonstrated that the HRE1 at position ,446 was essential for transcriptional activation of HSP70-2 promoter under hypoxic conditions. We also demonstrated that HIF-1, binds to the HSP70-2 promoter and the binding is specific, as revealed by HIF binding/competition and chromatin immunoprecipitation assays. Consequently, the upregulation of HSP70-2 enhanced the resistance of tumor cells to hypoxia-induced apoptosis. These findings provide a new insight into how tumor cells overcome hypoxic stress and survive, and also disclose a new regulatory mechanism of HSP70-2 expression in tumor cells. © 2008 Wiley-Liss, Inc. [source] ,6 integrin subunit mediates laminin enhancement of cisplatin-induced apoptosis in testicular tumor germ cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Maoulana Andjilani Abstract Our study demonstrates that laminin potentiates cisplatin-induced apoptosis in NCCIT, a testicular tumor germ cell line. When cultured on laminin, NCCIT cells displayed a significantly higher susceptibility to cisplatin-induced apoptosis than on plastic or on other ECM components including fibronectin, Type IV collagen and vitronectin. This high cisplatin sensitivity observed on NCCIT cell cultured on laminin was mediated by the ,6-integrin signaling. The knockdown of the ,6-integrin subunit by small interfering RNAs suppressed the higher cisplatin-sensitivity supporting the existence of a crosstalk between laminin-,6-integrin signaling and cisplatin-induced apoptosis. Our findings indicate that in cisplatin-treated NCCIT cells, the laminin-,6-integrin signaling induces the activation of executioner procaspase-3 and -6 as well as apoptosis-inducing factor (AIF) transcription and expression. The ability of integrin-mediated specific stroma,tumor cell interactions to modulate the chemosensitive phenotype of a tumor cell might provide new insights to overcome cisplatin resistance of tumor cells. © 2005 Wiley-Liss, Inc. [source] Enzymatic oxidation products of spermine induce greater cytotoxic effects on human multidrug-resistant colon carcinoma cells (LoVo) than on their wild-type counterpartsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2002Annarica Calcabrini Abstract The occurrence of resistance to cytotoxic agents in tumor cells, associated with several phenotypic alterations, is one of the major obstacles to successful anticancer chemotherapy. A new strategy to overcome MDR of human cancer cells was studied, using BSAO, which generates cytotoxic products from spermine, H2O2 and aldehyde(s). The involvement of these products in causing cytotoxicity was investigated in both drug-sensitive (LoVo WT) and drug-resistant (LoVo DX) colon adenocarcinoma cells. Evaluation of clonogenic cell survival showed that LoVo DX cells are more sensitive than LoVo WT cells. Fluorometric assay and treatments performed in the presence of catalase demonstrated that the cytotoxicity was due mainly to the presence of H2O2. Cytotoxicity was eliminated in the presence of both catalase and ALDH. Transmission electron microscopic observations showed more pronounced mitochondrial modifications in drug-resistant than in drug-sensitive cells. Mitochondrial functionality studies performed by flow cytometry after JC-1 labeling revealed basal hyperpolarization of the mitochondrial membrane in LoVo DX cells. After treatment with BSAO and spermine, earlier and higher mitochondrial membrane depolarization was found in LoVo DX cells than in drug-sensitive cells. In addition, higher basal ROS production in LoVo DX cells than in drug-sensitive cells was detected by flow-cytometric analysis, suggesting increased mitochondrial activity in drug-resistant cells. Our results support the hypothesis that mitochondrial functionality affects the sensitivity of cells to the cytotoxic enzymatic oxidation products of spermine, which might be promising anticancer agents, mainly against drug-resistant tumor cells. © 2002 Wiley-Liss, Inc. [source] Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease GJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2005Piotr Widlak Abstract Toward the end of the 20th and beginning of the 21st centuries, clever in vitro biochemical complementation experiments and genetic screens from the laboratories of Xiaodong Wang, Shigekazu Nagata, and Ding Xue led to the discovery of two major apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) and endonuclease G (Endo G). Both endonucleases attack chromatin to yield 3,-hydroxyl groups and 5,-phosphate residues, first at the level of 50,300 kb cleavage products and next at the level of internucleosomal DNA fragmentation, but these nucleases possess completely different cellular locations in normal cells and are regulated in vastly different ways. In non-apoptotic cells, DFF exists in the nucleus as a heterodimer, composed of a 45 kD chaperone and inhibitor subunit (DFF45) [also called inhibitor of CAD (ICAD-L)] and a 40 kD latent nuclease subunit (DFF40/CAD). Apoptotic activation of caspase-3 or -7 results in the cleavage of DFF45/ICAD and release of active DFF40/CAD nuclease. DFF40's nuclease activity is further activated by specific chromosomal proteins, such as histone H1, HMGB1/2, and topoisomerase II. DFF is regulated by multiple pre- and post-activation fail-safe steps, which include the requirements for DFF45/ICAD, Hsp70, and Hsp40 proteins to mediate appropriate folding during translation to generate a potentially activatable nuclease, and the synthesis in stoichiometric excess of the inhibitors (DFF45/35; ICAD-S/L). By contrast, Endo G resides in the mitochondrial intermembrane space in normal cells, and is released into the nucleus upon apoptotic disruption of mitochondrial membrane permeability in association with co-activators such as apoptosis-inducing factor (AIF). Understanding further regulatory check-points involved in safeguarding non-apoptotic cells against accidental activation of these nucleases remain as future challenges, as well as designing ways to selectively activate these nucleases in tumor cells. © 2005 Wiley-Liss, Inc. [source] The differential effects of the radioprotectant drugs amifostine and sodium selenite treatment in combination with radiation therapy on constituent bone cells, ewing's sarcoma of bone tumor cells, and rhabdomyosarcoma tumor cells in vitroJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 11 2008Bryan S. Margulies Abstract The purpose of this study was to determine the differential effects of therapeutic X-radiation on constituent bone cells relative to the pediatric tumor cells: Ewing's sarcoma of bone and rhabdomyosarcoma. In addition, the radioprotectant drugs amifostine and sodium selenite were administered to constituent bone cells and the two tumor cells to determine if the radioprotectants differentially protect bone cells while not benefiting the tumor cells. These studies are a necessary first step in determining the potential clinical benefit of radioprotective therapy. An established in vitro cell culture model employing both constituent bone cells (osteoblasts, primary bone marrow monocytes, osteoclasts chondrocytes, and endothelial cells) and the tumor cells lines (Ewing's sarcoma of bone and rhabdomyosarcoma) were exposed to irradiation, amifostine, and sodium selenite. Cells were then assayed for changes in cell number, cytotoxicity, mineralization, bone resorption, cell attachment, osteocalcin, caspase-3 expression, clonogenic survival, and alkaline phosphatase expression. Radiation therapy differentially decreased cell number; with osteoblasts being shown to be the least sensitive to irradiation, the tumor cells had an intermediate sensitivity and monocytes were the most sensitive. Both amifostine and sodium selenite protected chondrocytes and osteoblasts from the negative effects of irradiation, while not protecting the tumor cells. The pediatric tumor cell lines were generally more radiosensitive than the bone cells examined. The radioprotectant drugs amifostine and sodium selenite provided significant radioprotection to constituent bone cells while not protecting the tumor cells. Finally, amifostine and sodium selenite therapy provided an additional benefit beyond radioprotection by increasing cytotoxicity in nonirradiated and irradiated tumor cells. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1512,1519, 2008 [source] Improved therapeutic responses for liposomal doxorubicin targeted via thrombospondin peptidomimetics versus untargeted doxorubicinJOURNAL OF PEPTIDE SCIENCE, Issue 7 2010M. P. Rivera-Fillat Abstract New therapies in cancer treatment are focusing on multifaceted approaches to starve and kill tumors utilizing both antiangiogenic and chemotherapeutic compounds. In this work, we searched for a peptide vector that would home liposomes both to endothelial and tumor cells. [Abu6]TSPB and [Abu6]TSPA, aspartimide analogs of natural sequences of TSP-1 and TSP-2, respectively, were tested for adhesion of tumor and endothelial cells, in vivo and in vitro antiangiogenic effects, and in vivo antitumor action. Both peptides support the adhesion of both types of cells, but only [Abu6]TSPA inhibits the angiogenesis in vivo, and [Abu6]TSPA-targeted L -DOX decreases by 58% (P < 0.008) the HT29 tumor growth in nude mice. The improvement in the doxorubicin antitumor effect should be attributed to the antiangiogenic effect of [Abu6]TSPA, since [Abu6]TSPB, despite being a good ligand for both cell types, had no effect on tumor growth. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Correlation of visinin-like-protein-1 expression with clinicopathological features in squamous cell carcinoma of the esophagusMOLECULAR CARCINOGENESIS, Issue 8 2006Carla Wickborn Abstract EF-hand Ca2+ -sensor proteins are key molecules for transducing Ca2+ signals into physiological answers and changes in cytosolic Ca2+ concentration control a variety of cellular responses, including proliferation, migration, and differentiation, which are relevant for tumor progression. The Ca2+ -sensor visinin-like protein-1 (VILIP-1) has recently attracted major interest due to its putative tumor suppressor function. Whereas VILIP-1 is expressed in normal skin, it is downregulated in skin tumors in a murine tumor model. The aim of this study was to investigate the expression of the Ca2+ -sensor VILIP-1 in squamous cell carcinoma of the esophagus and to correlate expression levels with clinicopathological features of the tumor. We examined VILIP-1 expression in 54 specimens of esophageal squamous cell carcinomas and 24 normal esophagus tissues, with immunohistochemical staining and immunofluorescence co-staining techniques. VILIP-1 expression was completely lost or significantly reduced in esophageal tumor tissue compared with normal squamous epithelium. Correlation with clinicopathological features indicated that there was significantly less VILIP-1 expression in lymph node positive (N,=,1) versus lymph node negative (N,=,0) tumors (P,=,0.002). Although there was no significant difference between highly (G1), moderately (G2) and poorly differentiated (G3) tumors (P,=,0.177), VILIP-1 expression in tumors is significantly correlated with the depth of tumor invasion (P,=,0.028 between T1, T2, T3, and T4). In contrast, co-staining with the proliferation marker Ki-67 indicated no significant correlation with proliferation rates in tumors (Ki-67 index of the tumor). In summary, the expression of the Ca2+ -sensor VILIP-1 was found to be lost during development of squamous cell carcinoma of the esophagus. The protein expression level significantly correlates with invasive features, such as depth of tumor invasion and local lymph node metastasis, but not with proliferation rate of tumor cells. © 2006 Wiley-Liss, Inc. [source] Zebrafish embryo extracts promote sphere-forming abilities of human melanoma cell lineCANCER SCIENCE, Issue 8 2009Yi-Rang Na Sphere-forming abilities in culture condition are considered a hallmark of cancer stem-like cells, which represents tumor cell invasiveness and stem-like characteristics. We aimed to show that the sphere-forming subpopulation of human malignant melanoma cell line WM-266-4 acts differently to zebrafish embryo extracts compared with their bulk counterpart. Spheres were maintained in neural stem cell culture conditions. The embryos of zebrafish at specific developmental stages were collected and the extracts were purified under 100 kDa. Spheres were treated with embyo extracts and proliferation assay and immunocytochemistry were conducted. Spheroid cells expressed nestin and epidermal growth factor receptor (EGFR) but not melanoma antigen recognized by T-cells (MART)1, indicating their stem-like character. Zebrafish embryo extracts at 50% epiboly stage inhibited melanoma bulk cell proliferation in a dose-dependent manner. However, sphere-forming abilities were significantly enhanced under 1 µg/mL concentration of 50% epiboly stage embryo extract treatment. Our findings implicate that we should consider cell subsets of a different character from the tumor origin that can respond differently to exogenous substances or tumor microenvironments. We suggest that cancer research should consider both minor stem-like subpopulations and the other major bulk tumor cells. (Cancer Sci 2009) [source] CCAAT/enhancer binding protein-, promotes the survival of intravascular rat pancreatic tumor cells via antiapoptotic effectsCANCER SCIENCE, Issue 11 2007Yasuhito Shimizu A transcriptional factor, CCAAT/enhancer binding protein-, (C/EBP-,), regulates a variety of cell functions in normal and neoplastic cells. Although the involvement of C/EBP-, in metastasis has been demonstrated clinicopathologically in several types of human cancer, the mechanism by which it functions during the multistep process of metastasis remains largely unknown. We investigated the role of C/EBP-, in the intravascular step of hematogenous metastasis in a rat pancreatic tumor cell line, AR42J-B13, as this step profoundly affects metastatic efficiency. C/EBP-,-transfected AR42J-B13 (,B13) cells acquired considerable resistance against serum toxicity, which was primarily mediated by apoptosis in vitro. Upregulated expression of Bcl-2 and Bcl-xL was seen in ,B13 cells. Enhanced early survival of intraportally injected ,B13 cells in the BALB/c nu/nu male mice liver, detected by the mRNA of a vector-specific gene, was observed. Nick-end labeling analysis of the tumor-injected liver revealed significantly lower rates of apoptosis among intravascular ,B13 tumor cells than among empty vector-transfected AR42J-B13 (mB13) cells. Finally, intrasplenically injected ,B13 cells established a larger number of colonies in the liver than did the mB13 cells. These findings suggest that C/EBP-, may enhance hematogenous metastasis and its antiapoptotic effects may promote the survival of intravascular tumor cells. (Cancer Sci 2007; 98: 1706,1713) [source] Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2CANCER SCIENCE, Issue 7 2007Makoto Ishikawa Adiponectin, a circulating peptide hormone produced in adipose tissue, has been shown to be reduced in the plasma of patients with cancer, suggesting that this adipokine may be mechanically involved in the pathogenesis of adiposity-related carcinogenesis. In this study, we examined the expression of adiponectin receptors (AdipoR1 and AdipoR2) and assessed the function of adiponectin in gastric cancer. All of the six gastric cancer cell lines significantly expressed mRNA and protein of both receptors with variable levels. Addition of 30 µg/mL adiponectin potently induced apoptosis and inhibited the proliferation of AZ521 and HCG27. Down-regulation of either AdipoR1 or AdipoR2 by specific siRNA significantly suppressed the growth inhibitory effects of adiponectin in both cell lines. Moreover, a local injection of adiponectin markedly inhibited the growth of AZ521 inoculated subcutaneously in nude mice. Similarly, the continuous intraperitoneal infusion of adiponectin effectively suppressed the development of peritoneal metastasis of AZ521. Adiponectin negatively regulates the progression of gastric cancer cells possibly through both AdipoR1 and AdipoR2. Although adiponectin was already reported to have antiangiogenic effects, our results suggest that the antitumor effect of adiponectin was, at least partially, dependent on the direct effects on tumor cells. (Cancer Sci 2007; 98: 1120,1127) [source] Uveal melanoma and macular degeneration: molecular biology and potential therapeutic applicationsACTA OPHTHALMOLOGICA, Issue 8 2008Mario-Alexander Economou Abstract. Uveal melanoma is the most common primary intraocular malignant tumor in adults with 30% to 50% of patients that ultimately succumb to metastatic disease, mainly to the liver. (Shields et al. 1991) Although new diagnostic and therapeutic tools have been developed during the most recent years, only the eye conservation rate has been achieved, while the survival rate remains poor. The reason for this liver-homing is largely unknown, but it is conceivable that hepatic environmental factors may be implicated in the growth, dissemination, and progression of this malignancy. The insulin-like growth factor (IGF-1) that binds to the IGF-1 receptor (IGF-1R) is mainly produced in the liver. It has been shown to be crucial for tumor transformation, maintenance of malignant phenotype, promotion of cell growth, and prevention of apoptosis. (Baserga 1995) The hepatocyte growth factor/scatter factor (HGF/SF) is another growth factor produced in the liver and exerts its biological effects through binding to the plasma membrane receptor c-Met. The activation of this receptor by HGF/SF ligand can induce proliferation, motility, adhesion, and invasion of tumor cells. (Cruz et al. 2003) Metastasis is a process involving many components, including tumor cell adhesion, migration, extracellular matrix (ECM) proteolysis, and invasion. The tumor cells undergo intravasation, disperse via the vascular and the lymphatic systems, and finally extravasate to invade the secondary sites. In all these steps, proteolytic enzyme systems are involved, including the matrix metalloproteinase (MMP) system and the plasminogen activation system. The migration of a malignant cell through the ECM and the basement membrane requires proteolytic activities. (Stetler-Stevenson et al. 1993). Efforts to target the IGF-I system has been made with different types of cancer but not with uveal melanoma. [source] | |||||||||||||