|
| ||
|
|
||
Cancer Cells. (cancer + cells)
Selected AbstractsGenetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cellsGENES, CHROMOSOMES AND CANCER, Issue 12 2007Timon P. H. Buys The multidrug resistant (MDR) phenotype is often attributed to the activity of ATP-binding cassette (ABC) transporters such as P-glycoprotein (ABCB1). Previous work has suggested that modulation of MDR may not necessarily be a single gene trait. To identify factors that contribute to the emergence of MDR, we undertook integrative genomics analysis of the ovarian carcinoma cell line SKOV3 and a series of MDR derivatives of this line (SKVCRs). As resistance increased, comparative analysis of gene expression showed conspicuous activation of a network of genes in addition to ABCB1. Functional annotation and pathway analysis revealed that many of these genes were associated with the extracellular matrix and had previously been implicated in tumor invasion and cell proliferation. Further investigation by whole genome tiling-path array CGH suggested that changes in gene dosage were key to the activation of several of these overexpressed genes. Remarkably, alignment of whole genome profiles for SKVCR lines revealed the emergence and decline of specific segmental DNA alterations. The most prominent alteration was a novel amplicon residing at 16p13 that encompassed the ABC transporter genes ABCC1 and ABCC6. Loss of this amplicon in highly resistant SKVCR lines coincided with the emergence of a different amplicon at 7q21.12, which harbors ABCB1. Integrative analysis suggests that multiple genes are activated during escalation of drug resistance, including a succession of ABC transporter genes and genes that may act synergistically with ABCB1. These results suggest that evolution of the MDR phenotype is a dynamic, multi-genic process in the genomes of cancer cells. © 2007 Wiley-Liss, Inc. [source] Syntheses of 1-thio- D -xylose and D -ribose esters of diorganoarsinous acids and their anticancer activityHETEROATOM CHEMISTRY, Issue 2 2008Mingzhang Gao Several thio- D -xylose and D -ribose esters of dialkylarsinous acids have been synthesized. The crystal structure of 1- S -dimethylarsino-,- D -xylopyranose, 7a, has been obtained. Growth inhibition studies of about 60 strains of human cancer cells have been obtained in vitro for compounds 6a, 7a, 13, and 14. The results reveal that these compounds display a strong inhibition to subpanels of leukemia cells in vitro and high selectivity in inhibiting the growth of cancer cells. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:199,206, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20388 [source] Expression of ,CP-4 inhibits cell cycle progression and suppresses tumorigenicity of lung cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 7 2008Zafira Castaño Abstract The protein ,CP-4 (also known as hnRNP E4) is an RNA binding protein encoded by a gene at 3p21, one of the most common altered regions in lung cancer. It has been proposed that ,CP-4 may function as a lung tumor suppressor. Lack of ,CP-4 expression is frequent in highly proliferative lung tumors and correlates with ,CP-4 allele losses. The aim of this study was to evaluate the effect of ,CP-4 on the tumorigenic capacity of lung cancer cells. ,CP-4 expression was induced by transient transfection or stable infection with recombinant retroviruses. Induction of ,CP-4 expression caused cell cycle arrest in G2/M in 3 out of the 7 lung cancer cell lines studied, while no effect on apoptosis was observed. Anchorage-independent growth and invasion capacity of H1299 cells were significantly reduced by ,CP-4 induction. Tumorigenicity of H1299 cells in nude mice was greatly inhibited by the expression of ,CP-4. Moreover, induction of ,CP-4 expression in already established tumors resulted in a sudden growth arrest. Immunocytochemistry analysis of the xenograft tumors revealed an in vivo effect of ,CP-4 on cell proliferation and no effect on apoptosis. Finally, ,CP-4 showed a subcellular localization different from ,CP-4a, a splice variant that does not affect cell proliferation. In conclusion, expression of ,CP-4 can inhibit proliferation and tumorigenesis of lung cancer cells, both in vivo and in vitro, by delaying the progression of the cell cycle. © 2007 Wiley-Liss, Inc. [source] Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell lineINTERNATIONAL JOURNAL OF CANCER, Issue 2 2008Massimiliano Cariati Abstract The identification of mammary epithelial stem cells raises the hypothesis that these cells may be crucial in the pathogenesis of breast cancer. To further support this, a highly tumourigenic sub-population of cancer cells has recently been identified in primary and metastatic breast cancer samples. In this study, a sub-population of cells displaying features normally attributed to stem cells was identified within the breast cancer cell line MCF-7. This sub-population is capable of growth in anchorage-independent conditions as spherical organoids, displays resistance to proapoptotic agents and significantly greater tumourigenicity than its parental line, with as few as 1,000 cells able to form tumours in immunodeficient mice. Cells within this sub-population can be enriched by serial passages in anchorage-independence, and are characterized by over-expression of the adhesion molecule ,6-integrin. Alpha-6 integrin proves to be required for the growth and survival of these cells, as the knockdown of ITGA6 causes mammosphere-derived cells to lose their ability to grow as mammospheres and abrogates their tumourigenicity in mice. These findings support the existence of a highly tumourigenic sub-population in breast cancer cells. Furthermore, it shows ,6-integrin as a potential therapeutic target aimed at tumour-generating subsets of breast cancer cells. © 2007 Wiley-Liss, Inc. [source] The metastatic T-cell hybridoma antigen/P-selectin glycoprotein ligand 1 is required for hematogenous metastasis of lymphomasINTERNATIONAL JOURNAL OF CANCER, Issue 12 2007Geert Raes Abstract Using variants of the murine BW5147 lymphoma cell-line, we have previously identified 3 monoclonal antibodies (MAbs) that discriminate between metastatic and nonmetastatic BW5147-derived T-cell hybridomas and lymphomas, as well as BW5147-unrelated T-lymphomas. These MAbs were reported to recognize an identical membrane-associated sialoglycoprotein, termed "metastatic T-cell hybridoma antigen" (MTH-Ag). Here, we document that the expression pattern of the MTH-Ag on metastatic and nonmetastatic BW5147 variants correlates with that of the P-selectin glycoprotein ligand 1 (PSGL-1), a sialomucin involved in leukocyte recruitment to sites of inflammation. Moreover, the MAbs against the MTH-Ag recognize PSGL-1 when it is transfected in MTH-Ag-negative BW5147 variants, suggesting that the MTH-Ag is PSGL-1. Overexpression of MTH-Ag/PSGL-1 in MTH-Ag-negative BW5147 variants did not affect their in vivo malignancy. Yet, down-regulation of MTH-Ag/PSGL-1 expression on metastatic, MTH-Ag-positive BW5147 variants, using an RNA interference (RNAi) approach, resulted, in a dose-dependent manner, in a significant reduction of liver and spleen colonization and a delay in mortality of the recipient mice upon intravenous inoculation. Collectively, these results demonstrate that, although MTH-Ag/PSGL-1 overexpression alone may not be sufficient for successful dissemination and organ colonization, MTH-Ag/PSGL-1 plays a critical role in hematogenous metastasis of lymphoid cancer cells. © 2007 Wiley-Liss, Inc. [source] The E8 repression domain can replace the E2 transactivation domain for growth inhibition of HeLa cells by papillomavirus E2 proteinsINTERNATIONAL JOURNAL OF CANCER, Issue 10 2007Frank Stubenrauch Abstract Continuous expression of the human papillomavirus (HPV) oncoproteins E6 and E7 is required for the growth of cervical cancer cell lines. So far, only the overexpression of the wild type papillomavirus E2 protein has been shown to induce growth arrest in HPV18-positive HeLa cells by repressing E6/E7 transcription. Growth arrest by E2 requires the aminoterminal transcription activation domain in addition to the carboxyterminal DNA-binding domain. Several papillomaviruses such as the carcinogenic HPV31 express in addition to E2 an E8,E2C fusion protein in which the E8 domain, which is required for repression of replication and transcription, replaces the E2 activation domain. In this report, we demonstrate that the HPV31 E8,E2C protein is able to inhibit the growth of HeLa cells but not of HPV-negative C33A cervical cancer cells. Growth repression by E8,E2C correlates with repression of the endogenous HPV18 E6/E7 promoter and the reappearance of E6- and E7-regulated p53, pRb and p21 proteins, suggesting that E8,E2C inhibits growth by reactivating dormant tumor suppressor pathways. Growth inhibition requires an intact E8 repression domain in addition to the carboxyterminal E2C DNA binding domain. Chromatin immunoprecipitation experiments suggest that the E8 repression domain enhances binding to the HPV18 promoter sequence in vivo. In summary, our results demonstrate that the small E8 repression domain can functionally replace the large E2 transactivation domain for growth inhibition of HeLa cervical cancer cells. © 2007 Wiley-Liss, Inc. [source] Expression of plasminogen activator inhibitor-1, urokinase receptor and laminin ,-2 chain is an early coordinated event in incipient oral squamous cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Pia Lindberg Abstract Cancer cell invasion is facilitated by extracellular matrix degrading proteases such as plasmin. We have studied the expression of plasminogen activator inhibitor-1 (PAI-1) and urokinase receptor (uPAR) together with the ,2-chain of laminin-5 (lam-,2) by immunohistochemistry in 20 cases with incipient oral squamous cell carcinoma (SCC). PAI-1-positive neoplastic cells located at the tip of the putative invasive front of grade 1 (incipient) carcinoma were seen in 16 of the 20 cases (75%), whereas adjacent normal and dysplastic epithelium was PAI-1-negative. Clusters of putative invasive neoplastic cells located in the lamina propria were PAI-1-positive in areas with grade 2 incipient carcinoma as were invasive cancer cells in areas of grade 3,4 invasive carcinoma. uPAR immunoreactivity was strongly expressed in numerous stromal cells in the carcinoma area in all 20 lesions, while a few uPAR-positive stromal cells were found in areas with normal and dysplastic epithelium. uPAR-positive neoplastic cell islands located at the front of the lesions were seen in 15 of the 20 cases. The expression pattern of lam-,2 was very similar to that of PAI-1; however, lam-,2-positive neoplastic cells were only detected in 11 of the 20 cases (55%) in areas of grade 1 incipient carcinoma. Direct comparison of the 3 components revealed colocalization in neoplastic cell islands in both incipient and invasive SCC. Our results suggest that PAI-1 is a novel potential marker of initial invasion in oral SCC, and that the coordinated expression of PAI-1 with uPAR and lam-,2 sustain the features of the early invasive cancer cells. © 2006 Wiley-Liss, Inc. [source] Conjugated linoleic acid inhibits peritoneal metastasis in human gastrointestinal cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2006Hiroki Kuniyasu Abstract The effect of conjugated linoleic acid (CLA) on peritoneal metastasis was examined by in vitro treatment of cancer cells and mouse peritoneal metastasis models. First, cell growth of MKN28 human gastric cancer cells and Colo320 human colon cancer cells was suppressed by CLA in a dose-dependent manner with an increment in apoptosis. CLA significantly inhibited invasion into type IV collagen-coated membrane of MKN28 and Colo320 cells (p < 0.05). CLA-induced growth inhibition was recovered by the exposure to antisense S-oligodeoxynucleotide for peroxisome proliferator-activated receptor (PPAR)-, in both cell lines. BALB/c nu-nu mice were inoculated with MKN28 and Colo320 cells into their peritoneal cavity, and administrated with CLA intraperitoneally (weekly, 4 times). CLA treatment did not affect food intake or weight gain of mice. CLA treatment significantly decreased metastatic foci of both cells in the peritoneal cavity (p < 0.005). Survival rate in mice inoculated with MKN28 or Colo320 cells was significantly recovered by CLA treatment (p = 0.0025 and 0.0052, respectively). Protein production in MKN28 and Colo320 cells treated with CLA showed a decrease in epidermal growth factor receptor and transforming growth factor-, and an increase in Bax. These findings suggest that CLA inhibits metastasis of human gastric and colon cancer cells. © 2005 Wiley-Liss, Inc. [source] Interleukin-6 protects LNCaP cells from apoptosis induced by androgen deprivation through the Stat3 pathwayTHE PROSTATE, Issue 3 2004Soo Ok Lee Abstract BACKGROUND Elevated expression of interleukin-6 (IL-6) is implicated in the progression of hormone refractory prostate cancer. Previous studies demonstrated that IL-6 promotes androgen-independent growth of prostate cancer cells. In this study, the effect of IL-6 on apoptosis induced by androgen deprivation was investigated. METHODS The effect of IL-6 on apoptosis induced by androgen deprivation in LNCaP cells was examined by cell death ELISA and Western blot using cleaved poly (ADP-ribose) polymerase (PARP) and caspase-9, as well as Bcl-xL and phosphorylated Bad. The Stat3 in IL-6-mediated anti-apoptosis in prostate cancer cells was examined using either dominant-negative or constitutively activated Stat3 mutants. RESULTS Overexpression of IL-6 renders androgen sensitive LNCaP human prostate cancer cells more resistant to apoptosis induced by androgen deprivation. LNCaP cells undergo apoptosis after 72 hr of androgen deprivation, an outcome is largely absent in clones overexpressing IL-6 as measured by cell death ELISA and chromatin degradation assays. IL-6 over-expressing cells resulted in a significant decrease in the expression of cleaved PARP and cleaved caspase-9 as well as an increase in the expression of Bcl-xL and phosphorylated Bad. Addition of IL-6 antibody completely abolished the anti-apoptotic activity of IL-6. This protective effect of IL-6 was reversed by the expression of a dominant-negative Stat3 mutant, Stat3F. Furthermore, ectopic expression of a constitutively active Stat3 antagonized androgen deprivation-induced cell death of LNCaP cells. CONCLUSION These results indicate that IL-6 protects androgen sensitive LNCaP cells from apoptosis induced by androgen deprivation, and Stat3 activation play an important role in IL-6-mediated anti-apoptosis in prostate cancer cells. © 2004 Wiley-Liss, Inc. [source] Phosphatidylinositol 4,5-bisphosphate and PIP5-kinase I, are required for invadopodia formation in human breast cancer cellsCANCER SCIENCE, Issue 7 2010Hideki Yamaguchi Invadopodia are ventral cell protrusions formed in invasive cancer cells. Because invadopodia have extracellular matrix (ECM) degradation activity, they are thought to function in cancer invasion. In this study, we examined the roles of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and PI(4,5)P2 -producing enzymes in invadopodia formation in MDA-MB-231 human breast cancer cells. Immunofluorescence analysis showed that PI(4,5)P2 accumulates at invadopodia on the ventral cell surface. Injection of an anti-PI(4,5)P2 antibody inhibited invadopodia formation along with gelatin degradation activity. Sequestering of PI(4,5)P2 by overexpression of the phospholipase C (PLC) ,1-pleckstrin homology (PH) domain, a specific probe for PI(4,5)P2, also blocked invadopodia formation, while a mutated PLC,1-PH domain that lacks PI(4,5)P2 -binding activity had no effect. Cellular PI(4,5)P2 production is mainly mediated by type-I phosphatidylinositol 4-phosphate 5-kinase (PIP5KI) family proteins, which include PIP5KI,, I,, and I,. Real-time quantitative PCR analysis showed that PIP5KI, is a dominant isoform expressed in MDA-MB-231 cells. Knockdown of PIP5KI, by small-interfering RNA (siRNA) inhibited invadopodia formation and gelatin degradation. Immunofluorescence analysis revealed that endogenous PIP5KI, protein localizes at invadopodia, which is corroborated by the observation that exogenously expressed green fluorescent protein (GFP)-fused PIP5KI, protein also accumulates at gelatin degradation sites. These results indicate that localized production of PI(4,5)P2 by PIP5KI, is required for invadopodia formation and ECM degradation by human breast cancer cells. (Cancer Sci 2010) [source] Simvastatin inactivates ,1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cellsCANCER SCIENCE, Issue 6 2007Ikuko Takeda The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, also called statins, are commonly used as lipid-lowering drugs that inhibit cholesterol biosynthesis. An anticancer effect, as a pleiotropic function of certain statins, has been hypothesized. In the present study, we investigated the effect of simvastatin, one of the natural statins, on cell proliferation, cell cycle, invasive activity, and molecular expressions associated with cell,extracellular matrix adhesion, signal transduction, and DNA synthesis in Tu167 and JMAR cells from head and neck squamous cell carcinoma. The addition of simvastatin resulted in a dose-dependent inhibition of cell growth and migration into the extracellular matrix. Considerable morphological changes occurred after treatment with simvastatin, demonstrating loss of cell adhesion and disruption of actin filaments in cytoplasm. The inhibitory effect of simvastatin on cell proliferation seemed to be associated with cell cycle arrest and increased expression of p21, p27, and activated caspase-3. The expression of ,1-integrin, a counter adhesion for the extracellular matrix, phosphorylated FAK, and phosphorylated ERK was decreased by treatment with simvastatin. The proapoptotic effect of simvastatin was inhibited by treatment with mevalonate. cDNA microarray assay demonstrated that molecular changes resulting from treatment with simvastatin included the up-regulation of cell cycle regulators and apoptosis-inducing factors and the down-regulation of integrin-associated molecules and cell proliferation markers. Of down-regulated genes induced by simvastatin treatment, a significant depletion of thymidylate synthase was confirmed using western blot analysis. These results imply that simvastatin has the potential to be effective for the prevention of the growth and metastasis of cancer cells. (Cancer Sci 2007; 98: 890,899) [source] Carcinogenesis and transcriptional regulation through Maf recognition elementsCANCER SCIENCE, Issue 2 2007Hozumi Motohashi Many studies on carcinogenesis carried out early in the last century are united on the consensus that cancer is a genetic disease. Cancer cells typically display gene dysfunction and endogenous or exogenous insults resulting in gene dysfunction are often carcinogenic. Recent advances in stem cell biology added the new concept that cancer originates from a single cancer-initiating cell. To understand the molecular basis of carcinogenesis from the beginning to the full acquirement of malignancy, factors concerned with carcinogenesis were categorized into three groups: those guarding and stabilizing genomes, those regulating cell proliferation, and those conferring resistance to various micro-environmental stresses. One example of particular interest is the Keap1-Nrf2 system since, according to recent studies, it has turned out to be ambivalent. Nrf2 heterodimerizes with small Maf protein to strongly activate transcription through the Maf recognition element (MARE) and Keap1 is an inhibitory regulator of Nrf2. The genes regulated by Nrf2 are very important for cellular protection of the genome from xenobiotic and oxidative stresses and, consequently, for preventing carcinogenesis. This implies that enhancing Nrf2 activity is a promising method for thwarting cancer. On the contrary, the constitutive activation of Nrf2 due to mutations in the keap1 gene is characteristically observed in lung cancer cells, suggesting that induced expression of Nrf2 target genes favors the prevalence of cancer cells. (Cancer Sci 2007; 98: 135,139) [source] PP2C family members play key roles in regulation of cell survival and apoptosisCANCER SCIENCE, Issue 7 2006Shinri Tamura Although unlimited proliferation of cancer cells is supported by multiple signaling pathways involved in the regulation of proliferation, survival, and apoptosis, the molecular mechanisms coordinating these different pathways to promote the proliferation and survival of cancer cells have remained unclear. SAPK and integrin-ILK signaling pathways play key roles in the promotion of apoptosis and cell proliferation/survival, respectively. Studies of TNF,- and H2O2 -induced apoptosis revealed that ASK1, a component of the SAPK system, mediates the TNF, and H2O2 signaling of apoptosis. ASK1 is activated by autophosphorylation of a specific threonine residue (T845) following TNF, stimulation. Our recent studies indicate that PP2C,, a member of the PP2C family, associates with and inactivates ASK1 by dephosphorylating T845. In contrast, PP2C,/ILKAP, a second PP2C family member, activates ASK1 by enhancing cellular phosphorylation of T845. PP2C,/ILKAP also forms a complex with ILK1 to inhibit the GSK3,-mediated integrin-ILK1 signaling in vivo, inhibiting cell cycle progression. These observations raise the possibility that PP2C,/ILKAP acts to control the cross-talk between integrin-induced and TNF,-induced signaling pathways, inhibiting the former and stimulating the latter, thereby inhibiting proliferation and survival and promoting the apoptosis of cancer cells. (Cancer Sci 2006; 97: 563,567) [source] | ||||||||||