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  • Kim, Samyong  (4)
  • Medicine  (4)
  • 1
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    Online Resource
    The CXCR4 Antagonist AMD3100 Stimulates the Proliferation of Myeloma Cells.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 1701-1701
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1701-1701
    Abstract: AMD3100, an antagonist of the chemokine receptor CXCR4, is about to be used clinically for the peripheral mobilization of hematopoietic stem cells, especially in patients with lymphoma and multiple myeloma. However, AMD3100 has been shown to activate a G protein coupled with CXCR4 and thus acts as a partial CXCR4 agonist in vitro. Although stromal cell-derived factor-1 (SDF-1) alone has minimal or negligible effects on the growth and survival of myeloma cells in vitro, many reports are consistent with the SDF-1/CXCR4 axis being involved in the progression of myeloma. Therefore, it is necessary to address the question of whether AMD3100 functions as a partial agonist for CXCR4 in myeloma cells, before it is released for wide clinical application. In this study, we explored whether AMD3100 affects the proliferation and survival of myeloma cells in vitro. As demonstrated previously, AMD3100 markedly inhibited the SDF-1 induced chemotaxis of myeloma cells, including three cell lines (RPMI8226, U266, and ARH77 cells), and CD138+ primary human myeloma cells. AMD3100 also induced internalization of CXCR4. SDF-1 alone did not stimulate the proliferation of these myeloma cells, nor did it rescue the cells from apoptosis induced by serum deprivation. By contrast, AMD3100 at 10−5M enhanced the proliferation of all three myeloma cell lines in serum-free condition by up to 2-folds in 3-day cultures, which was abrogated by pretreating the cells with pertussis toxin (PTX). This phenomenon was also observed with CD138+ primary human myeloma cells. In addition, AMD3100 enhanced the proliferation of U266 and ARH77 cells induced by interleukin-6 (IL-6). AMD3100 partially inhibited the apoptosis induced by serum deprivation, and the anti-apoptotic effect of AMD3100 was further enhanced in the presence of IL-6. AMD3100 on its own induced the phosphorylation of Akt and ERK1/2 but not Stat3 and p38/MAPK in RPMI8226 and U266 cells. The phosphorylation was also inhibited by pretreating the cells with PTX. The signal blocking agents wortmannin, PD98056, SB203580, and rapamycin did not affect the AMD3100-induced proliferation of RPMI8226 cells. LY294002 at concentrations not inhibiting spontaneous proliferation (5 μM or less) did not affect AMD3100-induced proliferation of the cells. AG490 inhibited spontaneous proliferation and AMD3100-induced proliferation of the cells in a dose-dependent manner. Accordingly, the signal-blocking effects were unclear. However, these results show that AMD3100 partially overcame the strong growth inhibition of myeloma cells induced by AG490. Our results indicate that AMD3100 can induce the phosphorylation of signaling molecules and stimulate the proliferation of myeloma cells, through signaling via G-protein pathway.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.1701.1701
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
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  • 2
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    Online Resource
    Bortezomib Inhibits the Survival and Proliferation of Bone Marrow Stromal Cells Via Downregulation of the Chemokine CXCL12
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3951-3951
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3951-3951
    Abstract: Abstract 3951 Bortezomib is widely used for the treatment of multiple myeloma, based on findings that it induces apoptosis and strongly inhibits proliferation of myeloma cells. Bone marrow stromal cells (BMSCs) endow myeloma cells with survival and growth advantages. However, the influence of bortezomib on BMSCs is not well elucidated. In the present study, we examined the role of bortezomib in the survival and growth of BMSCs and its implications in myeloma cell biology. First, the effects of bortezomib on the proliferation and survival of the BMSCs were investigated. In a 3-day incubation of MS-5 murine BMSCs, the addition of 5 nM bortezomib significantly decreased cell proliferation as compared with controls (relative proliferation index, 2.1 ± 0.5 vs.1.6 ± 0.3 at 48 h; 3.5 ± 0.6 vs. 1.5 ± 0.2 at 72 h; both P 〈 0.05) and ≥ 50 nM bortezomib abolished cell proliferation. Consistent with these findings, bortezomib diminished the percentages of cells in S phase in a dose-dependent manner. Bortezomib (up to 500 nM) did not affect the survival of MS-5 cells for initial 24 h of incubation, whereas it markedly increased the percentages of annexin V-positive apoptotic cells after 72 h (54.7 ± 7.2% for 50 nM; 73.0 ± 10.4% for 500 nM; both P 〈 0.05 as compared with controls). Similar results were obtained with BMSCs from both healthy individuals (n = 4) and myeloma patients (n = 5). Next, we tested our hypothesis that downregulation of the chemokine CXCL12 may be involved in these phenomena. Knock-down of CXCL12 mRNA, using a short interfering RNA strategy, in BMSCs from both healthy individuals and myeloma patients resulted in a significant decrease in the survival and spontaneous proliferation of cells, indicating that CLCX12 is an autocrine survival and growth factor. Treating BMSCs with bortezomib at concentrations of 5, 50, and 500 nM for 24 h reduced CXCL12 mRNA expression to 50%, 20%, and 〈 10% of the control, respectively. In parallel, bortezomib decreased CXCL12 production in a dose-dependent manner, as evidenced in Western blotting and ELISA analysis. Additionally, CXCL12 serum levels in myeloma patients (n = 5) placed on bortezomib treatment were significantly decreased after 3 days of administration (2,256 ± 664 pg/mL vs. 1,283 ± 482 pg/mL; P 〈 0.05). The inhibition of BMSC survival and proliferation induced by 5 nM bortezomib was partially reversed by the addition of CXCL12. Finally, we tested whether bortezomib-induced alterations in BMSCs affect myeloma cell biology. Supernatants from 5 nM bortezomib-treated MS-5 cells induced chemotaxis of RPMI8226 myeloma cells to a much lower extent as compared with supernatants from non-treated cells (migration index, 7.3 ± 1.5 vs. 3.4 ± 1.1; P 〈 0.05). Additionally, short-term bortezomib treatment of MS-5 monolayers resulted in decreased localization of RPMI8226 cells under the monolayers as compared with non-treated ones. These results indicate that bortezomib inhibits the survival and growth of BMSCs via downregulation of CXCL12. The anti-myeloma effects of bortezomib may be exerted at least in part via modulation of BMSCs. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3951.3951
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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    detail.hit.zdb_id: 80069-7
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  • 3
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    Online Resource
    Abstract 1201: Hypoxia promotes not CXCR7 but CXCR4 expression and its biological activity in gastric cancer cell through activation of hypoxia-inducible factor-1β
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1201-1201
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1201-1201
    Abstract: Background: The chemokine receptor, CXCR4 and CXCR7, which bind with high affinity same chemokine CXCL12/SDF-1, are associated with the biological behavior in several kinds of cancer, but few studies have addressed the expression and regulation of CXCR4 and CXCR7 in gastric cancer. Methods: Gastric cancer cell line KATO III was subjected to hypoxia or normoxia. The expression of CXCR4 and CXCR7 were investigated using RT-PCR, Westerning blotting, and flow cytometry before and after hypoxic conditioning. The regulation of CXCR4 and CXCR7, and their biological effects by hypoxia were evaluated using gastric cancer cells transfected with hypoxia-inducible factor (HIF)-1α shRNA. Result: mRNA and proteins of both CXCR4 and CXCR7 were detectable by RT-PCR and Western blot analysis, respectively, in KATO III cells. A small population of KATO III cells expressed membrane CXCR4 and CXCR7 as determined by flow cytometry. Hypoxia up-regulated CXCR4 proteins and enhanced membrane expression of CXCR4 in human gastric cancer KATO III cells, which constitutively expressed membrane CXCR7 and CXCR4 in a steady state, as revealed by Western blotting and flow cytometry, respectively. In contrast, CXCR7 proteins remained unchanged under hypoxia, and promotion of CXCR7 surface expression on KATO III cells could not be demonstrated by flow cytometry. Hypoxia-induced expression of CXCR4 was mediated through activation of HIF-1α with phosphorylation of AKT and ERK, as revealed by HIF-1α knockdown using shRNA. The chemical inducer of HIF-1α, cobalt chloride, induced upregulation of CXCR4 in KATO III cells under normoxic conditions. In addition, KATO III cells exposed to hypoxic condition showed enhanced wound healing, transwell migration, and invasion in response to stromal cell-derived factor (SDF)-1α, a specific ligand for CXCR4. Conclusions: These findings provide evidences for differential regulation and different role of chemokine receptor, CXCR7 and CXCR4, in gastric cancer cell in vitro. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1201. doi:1538-7445.AM2012-1201
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1201
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    The Role of Endogenous Stromal Cell-Derived Factor-1 in the Survival and Growth of Acute Myeloid Leukemia Cells
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1502-1502
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1502-1502
    Abstract: Abstract 1502 Stromal cell-derived factor-1 (SDF-1) is constitutively expressed and produced by stromal cells in the bone marrow (BM). The protein exerts its functions by binding to its receptor CXCR4, thus guiding the homing of hematopoietic stem/progenitor cells and leukemia cells to the BM. CD34+ cells purified from normal adult peripheral blood have been shown to express and produce SDF-1, which exerted an antiapoptotic effect on CD34+ cell through an autocrine/paracrine loop. Acute myeloid leukemia (AML) cells have also been shown to express and produce SDF-1, but the role of SDF-1 in this context is largely unknown. Thus, the aim of the present study was to determine the function of SDF-1 produced by AML cells. Using siRNA technology, SDF-1 was knocked-down in AML cells and subsequent biological alterations occurring in the cells were evaluated in vitro. All AML cell lines used in this study (U937, K562, KG1a, HL-60 and MO7e) as well as primary CD34+ cells obtained from the BM of 5 patients with AML expressed SDF-1 mRNA at various levels, as revealed by semi-quantitative and real time RT-PCR analysis. SDF-1 was detected by Western blotting analysis and ELISA allowed for the detection of SDF-1 in the supernatants of cultures of AML cells grown for 3 days in a serum-free medium, indicating that AML cells, similar to normal CD34+ cells, are able to produce and secrete SDF-1. Exogenous SDF-1 (added at a concentration of up to 200 ng/mL) alone had no discernible effects on the survival or proliferation of either the cell lines or the primary CD34+ AML cells maintained in a serum-free medium, but was able to induce the internalization of CXCR4 and CXCR7. Transfection of five AML cell lines with SDF-1 siRNA diminished the SDF-1 mRNA levels by up to 90%. The knock-down cells were stable for at least 3 days. SDF-1 knock-down did not affect the serum deprivation-induced apoptosis of the cells. Cell surface expression of CXCR4 was not changed, whereas cytoplasmic CXCR4 was significantly upregulated along with the upregulation of SDF-1 mRNA. Neither cell surface nor cytoplasmic expression of CXCR7 was affected by the knock-down of SDF-1. Conversely, the knock-down of CXCR7, but not CXCR4, upregulated the SDF-1 mRNA expression in the transfected cells. No changes in the transmembrane and trnasendothelial migration of the knock-down cells were observed. In contrast, the knock-down of SDF-1 inhibited the spontaneous proliferation of the U937, K562, and KG1a cells by 20–30% during a 3-day incubation in a serum-free medium. These results indicate that endogenous SDF-1 of AML cells functions as an autocrine growth factor. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1502.1502
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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