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Malignant ascites is common in various types of cancers and is difficult to manage. Vascular endothelial growth factor (VEGF) has a pivotal role in malignant ascites. The matrix protein of vesicular stomatitis virus (VSVMP) has been shown to inhibit host gene expression and induce the apoptosis of cancer cells. The present study was designed to determine whether VSVMP suppresses the formation of ascites in ascites-producing peritoneal carcinomatosis. BALB/c female mice, 6-8 weeks old, bearing peritoneal tumors of H22 or MethA cells received an intraperitoneal administration of 50 μg VSVMP/250 μg liposome complexes, 50 μg empty plasmid/250 μg liposome complexes or 0.9% NaCl solution, respectively, every 2 days for 3 weeks. Administration of VSVMP resulted in a significant inhibition in ascites formation, improvement in health condition and prolonged survival of the treated mice. Decreased peritoneum osmolarity and reduced tumor vascularity coincided with dramatic reductions in the VEGF level in ascites fluid and plasma. Examination of floating tumor cells collected from the peritoneal wash revealed an apparently increased number of apoptotic cells and profound downregulation of VEGF mRNA in the VSVMP-treated mice. Our data indicate for the first time that in BALB/c mice bearing H22 or MethA cell peritoneal tumors, VSVMP may inhibit VEGF production and suppress angiogenesis, consequently abolishing ascites formation. [ABSTRACT FROM AUTHOR]

Changes in cell morphology are linked to many cellular events including cytokinesis, differentiation, migration and apoptosis. We recently showed that BNIP-Sα induced cell rounding that leads to apoptosis via its BNIP-2 and Cdc42GAP Homology (BCH) domain, but the underlying mechanism has not been determined. Here, we have identified a unique region (amino acid 133–177) of the BNIP-Sα BCH domain that targets RhoA, but not Cdc42 or Rac1 and only the dominant-negative form of RhoA could prevent the resultant cell rounding and apoptotic effect. The RhoA-binding region consists of two parts; one region (residues 133–147) that shows some homology to part of the RhoA switch I region and an adjacent sequence (residues 148–177) that resembles the REM class I RhoA-binding motif. The sequence 133–147 is also necessary for its heterophilic interaction with the BCH domain of the Rho GTPase-activating protein, p50RhoGAP/Cdc42GAP. These overlapping motifs allow tripartite competition such that overexpression of BNIP-Sα could reduce p50RhoGAP binding to RhoA and restore RhoA activation. Furthermore, BNIP-Sα mutants lacking the RhoA-binding motif completely failed to induce cell rounding and apoptosis. Therefore, via unique binding motifs within its BCH domain, BNIP-Sα could interact and activate RhoA while preventing its inhibition by p50RhoGAP. This concerted mechanism could allow effective propagation of the RhoA pathway for cell rounding and apoptosis.Oncogene (2006) 25, 2393–2408. doi:10.1038/sj.onc.1209274; published online 5 December 2005 [ABSTRACT FROM AUTHOR]

Researches regarding mitogen-inducible gene 6 (Mig-6) have confirmed its role as a tumor suppressor and progesterone resistance factor in endometrium. In this study, after confirming the downregulation of Mig-6 protein in endometrial carcinoma (EC) tissues, the expression of Mig-6 was upregulated in Ishikawa cells by pCMV6-Mig-6 plasmid. We observed the increased apoptosis, decreased proliferation and invasion potential of Ishikawa cells after upregulation of Mig-6. The proapoptosis ability of P4 significantly enhanced by 39.36%, the antiproliferation ability increased by 37.90% and the anti-invasion ability increased by 48.89%, suggesting the antiprogesterone resistance potential of Mig-6 in endometrium. In addition, the results suggested that Mig-6 may induce Ishikawa cell apoptosis through the mitochondrial pathway, inhibit cell proliferation via the extracellular signal-regulated kinase pathway and the anti-invasion potential may associate with matrix metalloproteinase (MMP)-2 and MMP-9 downexpression. Therefore, upregulation of Mig-6 may add a new strategy to suppress endometrial tumorigenesis and attenuate the progesterone resistance during P4 treatment. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-κB (NF-κB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-κB activity. Further investigation showed that Zac1 inhibits NF-κB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF-κB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis. [ABSTRACT FROM AUTHOR]

Background:Axl plays multiple roles in tumourigenesis in several cancers. Here we evaluated the expression and biological function of Axl in renal cell carcinoma (RCC).Methods:Axl expression was analysed in a tissue microarray of 174 RCC samples by immunostaining and a panel of 11 normal tumour pairs of human RCC tissues by western blot, as well as in RCC cell lines by both western blot and quantitative PCR. The effects of Axl knockdown in RCC cells on cell growth and signalling were investigated. The efficacy of a humanised Axl targeting monoclonal antibody hMAb173 was tested in histoculture and tumour xenograft.Results:We have determined by immunohistochemistry (IHC) that Axl is expressed in 59% of RCC array samples with moderate to high in 20% but not expressed in normal kidney tissue. Western blot analysis of 11 pairs of tumour and adjacent normal tissue show high Axl expression in 73% of the tumours but not normal tissue. Axl is also expressed in RCC cell lines in which Axl knockdown reduces cell viability and PI3K/Akt signalling. The Axl antibody hMAb173 significantly induced RCC cell apoptosis in histoculture and inhibited the growth of RCC tumour in vivo by 78%. The hMAb173-treated tumours also had significantly reduced Axl protein levels, inhibited PI3K signalling, decreased proliferation, and induced apoptosis.Conclusions:Axl is highly expressed in RCC and critical for RCC cell survival. Targeting Axl is a potential approach for RCC treatment. [ABSTRACT FROM AUTHOR]

The bridging integrator 1 (BIN1) tumor suppressor encodes multiple alternatively spliced isoforms implicated in DNA repair, cell-cycle control, apoptosis and membrane dynamics. BIN1 attenuation has been reported in several solid tumors; however, the role of BIN1 in lymphomagenesis remains unexplored. We recently demonstrated that BIN1 transcript levels are significantly downregulated in CD4+CD7− Sezary cells from patients with Sezary syndrome (SS), a subtype of cutaneous T-cell lymphoma (CTCL). We have now demonstrated that restored BIN1 expression in CTCL cells leads to a significant reduction in cell proliferation, an increase in spontaneous and Fas/Fas ligand (Fas/FasL)-induced apoptosis in vitro and inhibition of tumorigenic activity of CTCL cells in vivo. Interestingly, restoration of BIN1 expression in CTCL cells downregulates the expression of c-FLIP, an important inhibitor of Fas/FasL-mediated apoptosis, and activates the caspase cascade; these phenotypes can be rescued by knockdown of BIN1. Importantly, significantly reduced BIN1 expression and increased c-FLIP expression are observed in primary CTCL patient samples, and high BIN1 and low c-FLIP mRNA levels correlate with better survival rate in SS patients. These results indicate that BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP and that BIN1 deficiency may have an important role in CTCL pathogenesis by causing apoptosis resistance. Thus BIN1 and c-FLIP represent potential therapeutic targets in CTCL. [ABSTRACT FROM AUTHOR]

Glioma is the most common and fatal primary brain tumor. Thus far, therapeutic strategies to efficiently and specifically antagonize glioma are limited and poorly developed. Here we report that glia-enriched miR-135a, a microRNA that is dramatically downregulated in malig-nant glioma and correlated with the pathological grading, is capable of inducing mitochondria-dependent apoptosis of malignant glioma by regulating various genes including STAT6, SMAD5 and BMPR2, as well as affecting the signaling pathway downstream. Moreover, this lethal effect is selectively towards malignant glioma cells, but not neurons and glial cells, through a novel mechanism. Our findings suggest an important role of miR-135a in glioma etiology and provide a potential candidate for malignant glioma therapy. [ABSTRACT FROM AUTHOR]

Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, requiring novel anticancer strategies.Methods: Mantle cell lymphoma cell lines with known p53 status were treated with GUT-70, a tricyclic coumarin derived from Calophyllum brasiliense, and the biological and biochemical consequences of GUT-70 were studied.Results: GUT-70 markedly reduced cell proliferation/viability through G(1) cell cycle arrest and increased apoptosis, with greater sensitivity in mutant (mt)-p53-expressing MCL cells than in wild-type (wt)-p53-bearing cells. Mechanistically, GUT-70 showed binding affinity to heat-shock protein 90 (Hsp90) and ubiquitin-dependent proteasomal degradation of Hsp90 client proteins, including cyclin D1, Raf-1, Akt, and mt-p53. Depletion of constitutively overexpressed cyclin D1 by GUT-70 was accompanied by p27 accumulation and decreased Rb phosphorylation. GUT-70 induced mitochondrial apoptosis with Noxa upregulation and Mcl-1 downregulation in mt-p53 cells, but Mcl-1 accumulation in wt-p53 cells. Noxa and Mcl-1 were coimmunoprecipitated, and activated BAK. Treatment with a combination of GUT-70 and bortezomib or doxorubicin had synergistic antiproliferative effects in MCL cells that were independent of p53 status.Conclusion: GUT-70 has pronounced antiproliferative effects in MCL with mt-p53, a known negative prognostic factor for MCL, through Hsp90 inhibition. These findings suggest that GUT-70 has potential utility for the treatment of MCL. [ABSTRACT FROM AUTHOR]

Gene therapy promises to become an alternative choice for the treatment of hepatic cancer. In many cancers, the delivery of chimeric proteins by adenovirus vector has been reported to induce apoptosis. This study was performed to evaluate whether the recombinant adenovirus interleukin (IL)-24-Bax can induce apoptosis in hepatocellular carcinoma cells in vitro and in vivo. Several recombinant adenoviruses were constructed, and the expression of their encoded proteins was measured. The effects of the recombinant adenovirus on hepatocellular carcinoma cells and the normal hepatocyte cell line were investigated through cell viability and apoptosis assays after the cells were treated with Ad.Luc, Ad.IL-24, Ad.Bax or Ad.IL-24-Bax. The mechanism involved was also explored. A tumor-bearing mouse model was used to evaluate the effects of the adenovirus on tumor volume and cell apoptosis in vivo. Ad.IL-24-Bax selectively suppressed growth of hepatocellular carcinoma cells and induced apoptosis, but it had little influence on the normal hepatocytes. The mechanism of this response may include the effect of the 10HRE/VEGF385 promoter and the synergistic effect of IL-24 and Bax. Ad.IL-24-Bax also suppressed tumor growth in nude mice and induced apoptosis. Ad.IL-24-Bax may be a useful tool for gene therapy of hepatic cancer. [ABSTRACT FROM AUTHOR]

Our previous studies indicate that reduction of lipocalin 2 (mouse 24p3) expression by either anti-sense or siRNA approaches strongly reduces the overgrowth of BCR-ABL+ mouse myeloid 32D in marrow and spleen of NOD/SCID mice. In this study, we used the mouse bone marrow transplant model to further explore the role of 24p3 in BCR-ABL-induced leukemia. Consistent with our previous findings, when using non-irradiated mice as recipient, donor marrow cells expressing BCR-ABL but lacking 24p3 did not cause leukemia or any disease after 75 days, whereas all mice receiving wild type BCR-ABL donor cells died with CML-like disease. An agar clone of the BCR-ABL+ human CML cell line K562 (C5) that secretes relatively high levels of lipocalin 2 (human NGAL) induced suppression of hematopoiesis in spleen and marrow of mice, leading to early death in contrast to parental K562 or K562 clone (C6) expressing low amounts of NGAL. Compared with K562 cells, overexpressing NGAL in K562 led to a higher apoptosis rate and an atrophy phenotype in the spleen of the inoculated mice. Plasma from both leukemic mice and CML patients showed elevated lipocalin 2 levels compared with healthy individuals. Moreover, we found that a primary stable cell line from wild-type mouse marrow cells expressing BCR-ABL caused solid tumors in nude mice whereas a similar BCR-ABL+ cell line from 24p3 null mice did not. These findings demonstrate that lipocalin 2 has at least two functions related to tumorigenesis, one involving apoptosis induction of normal hematopoietic cells and the other being tissue invasion by leukemia cells.Oncogene (2008) 27, 6110–6119; doi:10.1038/onc.2008.209; published online 28 July 2008 [ABSTRACT FROM AUTHOR]

Erythroid differentiation-associated gene (EDAG) is considered to be a human hematopoiesis-specific gene. Here, we reported that downregulation of EDAG protein in K562 cells resulted in inhibition of growth and colony formation, and enhancement of sensitivity to erythroid differentiation induced by hemin. Overexpression of EDAG in HL-60 cells significantly blocked the expression of the monocyte/macrophage differentiation marker CD11b after pentahydroxytiglia myristate acetate induction. Moreover, overexpression of EDAG in pro-B Ba/F3 cells prolonged survival and increased the expression of c-Myc, Bcl-2 and Bcl-xL in the absence of interleukin-3 (IL-3). Furthermore, we showed that EDAG enhanced the transcriptional activity of nuclear factor-kappa B (NF-?B), and high DNA-binding activity of NF-?B was sustained in Ba/F3 EDAG cells after IL-3 was withdrawn. Inhibition of NF-?B activity resulted in promoting Ba/F3 EDAG cells death. These results suggest that EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of NF-?B.Cell Death and Differentiation (2004) 11, 1299-1308. doi:10.1038/sj.cdd.4401490 Published online 27 August 2004 [ABSTRACT FROM AUTHOR]