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At least 163 records · Page 9Linked to original sources
PubMed2005

Significance of survivin mRNA expression in prognosis of neuroblastoma.

Neuroblastoma (NB) is the most common malignant solid tumor in childhood, and among all childhood malignancies is second in prevalence only to leukemia. In NB we need to both make an accurate diagnosis and rapidly analyze the expression of genetic prognostic factors such as MYCN, H-ras, and trkA. Moreover, it has recently become important to analyze the expression of survivin mRNA, a member of the inhibitor of apoptosis protein family. Expression of the survivin gene is related to tumorigenesis and inhibition of apoptosis in some malignant tumors. We investigated its expression by reverse transcription-polymerase chain reaction (RT-PCR) in NB cell lines (SK-N-SH, NB-39, and IMR-32), two normal blood cell samples, and 13 clinical NB tumor samples. All three NB cell lines had high levels of mRNA expression for this gene, but normal blood cells had no expression. We detected expression of survivin mRNA in 7 of the 13 NB tumor samples (54%). Two NB patients were in stage I disease, 6 in stage II, and 5 in stage IV(A). Quantitative analysis by RT-PCR revealed that the ratio between survivin mRNA and human glyceraldehyde-3-phosphate dehydrogenase (h-GAPDH) mRNA was very low in stages I and II (0-0.017). In contrast, in advanced NBs (stage IV(A)) the ratio was much higher (0-0.050). The prognoses of the three patients in the advanced stage who had high ratios of expression were poor. A high level of expression of survivin mRNA indicates a high grade of malignancy, high likelihood of recurrence, and poor prognosis.

Cell Line, Tumor↗
PubMedDate not supplied

MRP expression of testicular cancers and its clinical relevance.

BACKGROUND: The expression of a multidrug resistance associated protein (MRP) has been investigated in a variety of human tumors. However, there is a lack of data regarding its expression in germ cell testicular tumors (GCTTs). PATIENTS AND METHODS: MRP expression was examined by immunohistochemistry (IHC) using mouse monoclonal antibody (MRPm6) against human MRP in 56 testis cancer specimens. This antigen was also correlated with the histology, metastatic behavior, clinical stage and tumor suppressor protein p53 immunostaining of GCTTs. RESULTS: All testis tumors, regardless of their histology, metastatic status and clinical stage gave positive signals. MRP was positive not only in the cytoplasm but, very interestingly, in the nuclei. CONCLUSION: Our results suggested that ala GCTTs express high levels of MRP protein with no relation to any of clinicopathological variables investigated here. Since germ cell tumors are very sensitive to chemotherapy, the role of MRP as mediator of drug resistance seems unconvincing in this malignancy. MRP is located in the cytoplasm and the nuclei of tumor cells and may be involved in transportation and/or redistribution certain substrates from the nucleus to the cytoplasm.

ATP-Binding Cassette Transporters↗
PubMed1997

BCL-2: the pendulum of the cell fate.

The homeostasis of normal tissues is a balance between cell proliferation and cell death. Alterations of both pathways contribute to a clonal expansion of cancer cells. Bcl-2 and its family play an important role in the regulation of the apoptotic pathway. Apoptosis or programmed cell death is an active form of cell suicide that is characterized by specific morphological and biochemical events. These include cleavege of genomic DNA into oligonucleosome-length DNA fragments by endonucleases, chromatin condensation and marginalization, nuclear fragmentation, plasma membrane blebbing, and cell shrinkage. Though the role of apoptosis is clearly defined in the maintaining of physiological tissue homeostasis, several pathological conditions and external factors cause apoptosis. Anticancer drugs and radiation, two of the most important tools in the cancer treatment, cause apoptotic cell death. The understanding of the mechanisms underlying the regulation of the apoptosis in response to different types of DNA damage might provide relevant information to improve cancer treatment. In this review we mainly discuss bcl-2 and its partners in human cancers and how their disregulation might contribute to the development and the difficult treatment of cancer.

Animals↗
PubMed2004

Expression of PTEN in malignant and non-malignant human prostate tissues: comparison with p27 protein expression.

The role of the putative tumour suppressor PTEN in prostate carcinogenesis is controversial. There are conflicting data regarding the rate of its gene inactivation, the role of transcriptional and post-transcriptional factors, as well as its relationship to tumour progression and to the potential downstream regulator, the cell-cycle inhibitor p27. The present study has assessed the in situ expression of PTEN mRNA and protein in 26 prostate intraepithelial neoplasias (PINs), 58 primary prostate carcinomas, and 15 metastases. Although there was a correlation between PTEN mRNA and protein expression, mRNA detection exceeded detection of protein in 19% of PINs and 30% of all invasive tumours. Using RT-PCR and western blotting on microdissected tissue, this discrepancy was attributed, at least in part, to transcription of the PTEN pseudo-gene, which lacks introns. Total or partial loss of PTEN protein occurred with tumour progression but this association was not statistically significant. Analysing the relationship between PTEN and p27 protein expression on consecutive sections by immunohistochemistry, the results do not support a direct link between the two oncosuppressors, other than an associated loss of expression in advanced tumour stages. However, in the basal cells of prostate glands and in most PINs, an inverse relationship was observed between PTEN and p27. This may reflect the existence of a functional balance that controls the cell cycle in prostatic epithelium and that is probably disturbed in invasive tumour cells.

Adenocarcinoma↗
PubMed2003

Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model.

It is well established that high expression of the antiapoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL can significantly contribute to chemoresistance in a number of human malignancies. Much less is known about the role the more recently described Bcl-2 family member Mcl-1 might play in tumor biology and resistance to chemotherapy. Using an antisense strategy, we here address this issue in melanoma, a paradigm of a treatment-resistant malignancy. After in vitro proof of principle supporting an antisense mechanism of action with specific reduction of Mcl-1 protein as a consequence of nuclear uptake of the Mcl-1 antisense oligonucleotides employed, antisense and universal control oligonucleotides were administered systemically in combination with dacarbazine in a human melanoma SCID mouse xenotransplantation model. Dacarbazine, available now for more than three decades, still remains the most active single agent for treatment of advanced melanoma. Mcl-1 antisense oligonucleotides specifically reduced target protein expression as well as the apoptotic threshold of melanoma xenotransplants. Combined Mcl-1 antisense oligonucleotide plus dacarbazine treatment resulted in enhanced tumor cell apoptosis and led to a significantly reduced mean tumor weight (mean 0.16 g, 95% confidence interval 0.08-0.26) compared to the tumor weight in universal control oligonucleotide plus dacarbazine treated animals (mean 0.35 g, 95% confidence interval 0.2-0.44) or saline plus dacarbazine treated animals (mean 0.39 g, 95% confidence interval 0.25-0.53). We thus show that Mcl-1 is an important factor contributing to the chemoresistance of human melanoma in vivo. Antisense therapy against the Mcl-1 gene product, possibly in combination with antisense strategies targeting other antiapoptotic Bcl-2 family members, appears to be a rational and promising approach to help overcome treatment resistance of malignant melanoma.

Animals↗
PubMed2006

Cyclin E but not bcl-2, bax or mcl-1 is differentially expressed in ZAP 70-positive and ZAP 70-negative B-CLL cells.

The clinical course of chronic lymphocytic leukemia is variable. While some patients have indolent disease, others require aggressive treatment within a short time after diagnosis. Differences in the expression of proteins regulating cell cycle and apoptosis may be responsible for the heterogeneous course of the disease. Recently, protein ZAP 70 [zeta-chain (T-cell receptor) associated protein kinase 70 kDa] has been found to be differentially expressed within two biologic subgroups, characterized by the presence or absence of somatic mutations in specific immunoglobulin heavy-chain variable region genes. In the present work, we analyzed highly purified B-CLL cells from 60 patients for ZAP 70 expression and the expression of cyclin E, bcl-2, bax, and mcl-1 as well as the ratios of bcl-2/bax and mcl-1/bax. The results indicate that cyclin E is expressed significantly higher in ZAP 70-positive as in ZAP 70-negative samples. We did not observe significant differences within the expression of Bcl-2 family member proteins. We conclude that higher cyclin E expression in samples of ZAP 70-positive patients may reflect a larger proliferating compartment in vivo compared to ZAP 70-negative patients and that cyclin E may add prognostic information in this context for patients with B-CLL.

Adult↗
PubMed1992

Epithelial polarity and cell separation in the neoplastic l(1)dlg-1 mutant of Drosophila.

Lethal (1) discs-large-1 [l(1)dlg-1] is a non-epithelial overgrowth or neoplastic mutant of Drosophila, which results in tumor-like imaginal discs and enlarged larvae that never pupariate. In an ultrastructural analysis we found that the wing discs develop convoluted monolayers of epithelial cells characterized by well-defined apical-basal polarity and that these layered cells secrete large amounts of basement membrane material. Immuno-EM indicates that Drosophila laminin and collagen are components of this matrix. Late in development clusters or 'rosettes' of separated cells lacking cell-cell junctions and apical-basal polarity form. In in vitro culture experiments l(1)dlg-1 wing discs did not respond to a pulse of exogenous ecdysone by secreting cuticle or losing basement membrane as normal discs do. Our observations are consistent with the hypothesis that cell-cell interaction and communication is required for termination of disc cell proliferation, which must occur prior to a cellular response to ecdysone.

Animals↗
PubMed2000

Immunohistochemical detection of Bcl-2 in Kaposi's sarcoma lesions varies according to histopathologic stage, whereas expression of Bcl-x and Mcl-1 differs according to human immunodeficiency virus serologic status of patients.

Expression of Bcl-2, Bcl-x, and Mcl-1 was immunohistochemically evaluated in 33 cases of Kaposi's sarcoma (KS) of the skin. Of these, classic KS (C-KS) accounted for 17 cases (10 in plaque stage and 7 in tumor stage) and acquired immunodeficiency syndrome-associated KS (AIDS-KS) accounted for 16 cases (8 in plaque stage and 8 in tumor stage). In both C-KS and AIDS-KS, Bcl-2 immunoreaction correlated with progression stage, its average score intensity being more than 2-fold in tumors than in plaques. In contrast, Bcl-x and Mcl-1 staining intensity was unrelated to progression stage but was dependent on human immunodeficiency virus infection status. Thus, whereas Bcl-x expression was stronger in C-KS cases, Mcl-1 immunostaining was more intense in AIDS-KS instances. These findings indicate that in cutaneous KS, some Bcl-2 family proteins exhibit differential expressions that are dependent on either progression stage or human immunodeficiency virus infection status.

Acquired Immunodeficiency Syndrome↗
PubMed2006

PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR.

Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.

Animals↗
PubMed2003

A flow cytometric method to detect apoptosis-related protein expression in minimal residual disease in acute myeloid leukemia.

Minimal residual disease (MRD) cells are thought to be responsible for the persistence and relapse of acute myeloid leukemia (AML). Flow cytometric MRD detection by the establishment of a leukemia-associated phenotype (LAP) at diagnosis can be used in 80% of AML patients, allowing detection and functional characterization of MRD in follow-up bone marrow. One of the mechanisms contributing to inefficient chemotherapy is apoptosis resistance. Measuring apoptosis parameters in MRD cells will help to unravel the importance of apoptosis resistance in AML. We therefore developed a four-color flow cytometry method that enables establishment of apoptosis-related protein expression such as Bcl-2, Bcl-x(L), Mcl-1 and Bax at diagnosis and in MRD. Firstly, validation of this assay using Western blot analysis in five leukemia cell lines showed a significant correlation (R=0.70: P<0.0001). Secondly, the influence of the permeabilization procedure on LAP expression was investigated in 38 AML samples at diagnosis and in 42 MRD samples. Quantification of the frequency of LAP+ cells with and without permeabilization showed no significant differences (diagnosis: P= 0.57, follow-up: P= 0.43). The flow cytometric protocol thus enables analysis of apoptosis-related proteins at different stages of the disease, which will lead to a better understanding of the role of apoptosis resistance in the emergence of MRD in AML.

Acute Disease↗
PubMed2006

Regulation of survivin expression by IGF-1/mTOR signaling.

Survivin is a dual regulator of cell proliferation and cell viability overexpressed in most human tumors. Although strategies to lower survivin levels have been pursued for rational cancer therapy, the molecular circuitries controlling survivin expression in tumors have not been completely elucidated. Here, we show that stimulation with insulin-like growth factor-1 (IGF-1) results in increased survivin expression in prostate cancer cells. This response is independent of de novo gene transcription, changes in mRNA expression or modifications of survivin protein stability. Instead, IGF-1 induced persistence and translation of a pool of survivin mRNA, in a reaction abolished by the mTOR (mammalian target of rapamycin) inhibitor, rapamycin. Forced expression of the mTOR target p70S6K1 reproduced the increase in survivin expression in prostate cancer cells, whereas acute ablation of endogenous p70S6K1 by small interfering RNA downregulated survivin levels. Rapamycin, alone or in combination with suboptimal concentrations of taxol reduced survivin protein levels, and decreased viability of prostate cancer cells. Therefore, IGF-1/mTOR signaling elevates survivin in prostate cancer cells via rapid changes in mRNA translation. Antagonists of this pathway may be beneficial to lower an antiapoptotic threshold maintained by survivin in prostate cancer.

Animals↗
PubMed2005

Oncogenes as novel targets for cancer therapy (part IV): regulators of the cell cycle and apoptosis.

This is the final part of a four-part serial review on oncogenes and their potential use as targets for cancer therapy. Previous sections discussed various categories of oncogenes (growth factors, tyrosine kinases, intermediate signaling molecules, and transcription factors) and the advances made in various strategies being used to alter their actions. This part describes four oncogenes, MDM2, BCL2, XIAP, and Survivin, that are involved in regulation of the cell cycle and apoptosis.

Animals↗