| 1. |
- Wegiel, Barbara, et al.
(author)
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Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells
- 2014
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In: Cell Death and Disease. - : Nature Publishing Group. - 2041-4889. ; 5
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Journal article (peer-reviewed)abstract
- Critical functions of the immune system are maintained by the ability of myeloid progenitors to differentiate and mature into macrophages. We hypothesized that the cytoprotective gas molecule carbon monoxide (CO), generated endogenously by heme oxygenases (HO), promotes differentiation of progenitors into functional macrophages. Deletion of HO-1, specifically in the myeloid lineage (Lyz-Cre:Hmox1flfl), attenuated the ability of myeloid progenitors to differentiate toward macrophages and decreased the expression of macrophage markers, CD14 and macrophage colony-stimulating factor receptor (MCSFR). We showed that HO-1 and CO induced CD14 expression and efficiently increased expansion and differentiation of myeloid cells into macrophages. Further, CO sensitized myeloid cells to treatment with MCSF at low doses by increasing MCSFR expression, mediated partially through a PI3K-Akt-dependent mechanism. Exposure of mice to CO in a model of marginal bone marrow transplantation significantly improved donor myeloid cell engraftment efficiency, expansion and differentiation, which corresponded to increased serum levels of GM-CSF, IL-1α and MCP-1. Collectively, we conclude that HO-1 and CO in part are critical for myeloid cell differentiation. CO may prove to be a novel therapeutic agent to improve functional recovery of bone marrow cells in patients undergoing irradiation, chemotherapy and/or bone marrow transplantation.
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| 2. |
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| 3. |
- Wegiel, Barbara, et al.
(author)
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Molecular Pathways in the Progression of Hormone-Independent and Metastatic Prostate Cancer
- 2010
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In: Current Cancer Drug Targets. - 1873-5576. ; 10:4, s. 392-401
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Research review (peer-reviewed)abstract
- Once prostate cancer becomes castration resistant, cancer cells may rapidly gain the ability to invade and to metastasize to lymph nodes and distant organs. The progression through hormone-dependent to hormone-independent/castration-resistant and metastatic PCa is poorly understood. In this review paper, we provide an overview on the cellular and molecular mechanisms underlying the process of tumor cell invasion and metastasis in prostate cancer. We specifically presented the most recent findings on the role of multiple cellular signaling pathways including androgen receptor (AR), mitogen-activated protein kinases (MAPK), Akt, transforming growth factor beta (TGF beta), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in the development of hormone-independent/castration-resistant prostate cancer. In addition, we also discussed the recent findings on signatures of gene expression during prostate cancer progression. Our overviews on the novel findings will help to gain better understanding of the complexity of molecular mechanisms that may play an essential role for the development of castration-resistant and metastatic prostate cancer. It will also shed light on the identifying specific targets and design effective therapeutic drug candidates.
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| 4. |
- Wegiel, Barbara, et al.
(author)
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Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth
- 2013
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In: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 73:23, s. 7009-7021
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Journal article (peer-reviewed)abstract
- One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion.
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| 6. |
- Wegiel, Barbara, et al.
(author)
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Multiple cellular mechanisms related to cyclin A1 in prostate cancer invasion and metastasis
- 2008
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In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:14, s. 1022-1036
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cyclin A1 is a cell cycle regulator that has been implicated in the progression of prostate cancer. Its role in invasion and metastasis of this disease has not been characterized.METHODS: Immunohistochemistry and cDNA microarray analyses were used to assess protein and mRNA expression of cyclin A1 and proteins with roles in metastasis, including vascular endothelial growth factor (VEGF), metalloproteinase 2 (MMP2), and MMP9, in human prostate cancer. Transient transfection and infection with viral vectors expressing cyclin A1 and short hairpin RNA (shRNA) targeting cyclin A1 were used to study the effects of altered cyclin A1 expression in PC3 prostate cancer cells. The BrdU assay, annexin V staining, and invasion chambers were used to examine cyclin A1 effects on proliferation, apoptosis, and invasion, respectively. The role of cyclin A1 and androgen receptor (AR) in transcription of VEGF and MMP2 was assessed by promoter mutation and chromatin immunoprecipitation. The effect of cyclin A1 expression on tumor growth and metastasis was analyzed in a mouse model of metastasis. All statistical tests were two-sided.RESULTS: Cyclin A1 protein and mRNA expression were statistically significantly higher in prostate cancers than in adjacent benign tissues. A statistically significant correlation between expression of cyclin A1 and of MMP2, MMP9, and VEGF was observed in prostate tumors from 482 patients (P values from Spearman rank correlation tests < .001). PC3 cells that overexpressed cyclin A1 showed increased invasiveness, and inhibition of cyclin A1 expression via shRNA expression reduced invasiveness of these cells. Eight of 10 mice (80%) bearing PC3 cells overexpressing cyclin A1 had infiltration of tumor cells in lymph node, liver, and lung, but all 10 mice bearing tumors expressing control vector were free of liver and lung metastases and only one mouse from this group had lymph node metastasis (P values from Fisher exact tests < .001). Cyclin A1, in concert with AR, bound to and increased expression from the VEGF and MMP2 promoters.CONCLUSIONS: Cyclin A1 contributes to prostate cancer invasion by modulating the expression of MMPs and VEGF and by interacting with AR.
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