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  • Online Resource  (9)
  • American Association for Cancer Research (AACR)  (9)
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  • American Association for Cancer Research (AACR)  (9)
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  • 1
    Online Resource
    Online Resource
    Triptolide Inhibits MDM2 and Induces Apoptosis in Acute Lymphoblastic Leukemia Cells through a p53-Independent Pathway
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 2 ( 2013-02-01), p. 184-194
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 2 ( 2013-02-01), p. 184-194
    Abstract: Triptolide, a natural product derived from the Chinese plant Tripterygium wilfordii, is reported to exhibit antitumor effects in a broad range of cancers. The antitumor activity of triptolide is associated with its biologic activities, as it inhibits various proproliferative or antiapoptotic factors that are dominantly expressed in given types of cancer cells. Herein, we show that triptolide induced apoptosis in a subgroup of acute lymphoblastic leukemia (ALL) cells overexpressing the MDM2 oncoprotein by inhibiting MDM2 expression. More specifically, we found that triptolide inhibited MDM2 at the transcriptional level by suppressing its mRNA synthesis. This MDM2 inhibition led in turn to increased levels of p53 protein; however, p53 functionality was not activated due to the fact that triptolide-treated cells lacked induction of p21 and PUMA as well as in G1 cell-cycle arrest. Triptolide-mediated downregulation of MDM2 increased inhibition of X-linked inhibitor of apoptosis protein (XIAP), its translational target, in a manner distinct from reactions to cellular stress and DNA-damaging agent ionizing radiation that induce XIAP due to p53-activated MDM2. These results suggest that increased inhibition of XIAP due to downregulation of MDM2 may play a critical role in triptolide-induced apoptosis in MDM2-overexpressing cancers. Mol Cancer Ther; 12(2); 184–94. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-12-0425
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Abstract 3162: MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3162-3162
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3162-3162
    Abstract: The MYCN gene plays a critical role in determining the clinical behavior of neuroblastoma. Genomic amplification occurs in high-risk subsets, but it remains unclear how MYCN expression is regulated in human neuroblastomas. Here, we report that the expression of MYCN is regulated by the oncoprotein MDM2 at the post-transcriptional level. Ectopic overexpression of MDM2 or an increase in the cytoplasmic levels of endogenous MDM2 by inhibition of PI3K/Akt activity enhanced both MYCN mRNA and protein expression. UV cross-linking and RNA-protein binding assays demonstrated that the C-terminal RING domain of MDM2 bound to AU-rich elements within the 3’-untranslated region (3’-UTR) of MYCN mRNA. Furthermore, gene transfection and reporter assay confirmed that MDM2 increased MYCN 3’-UTR-mediated mRNA stability and induced translation of reporter luciferase. Conversely, MDM2 silencing by specific siRNA rendered the MYCN mRNA unstable, reducing the abundant MYCN protein found in MYCN-overexpressing neuroblastoma cell lines, which are a consequence of gene amplification. Importantly, silencing of MDM2 in MYCN-amplified neuroblastoma cell lines resulted in a remarkable inhibition of cell growth and induction of cell death, through a p53-independent pathway. These results indicate that MDM2 plays a p53-independent role in regulating MYCN mRNA stabilization and protein translation, and suggest that MDM2-mediated MYCN expression is an important mechanism for tumor growth and for disease progression, specifically in MYCN-associated neuroblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3162.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3162
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Inhibition of MDM2 by a Rhein-Derived Compound AQ-101 Suppresses Cancer Development in SCID Mice
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 2 ( 2018-02-01), p. 497-507
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 2 ( 2018-02-01), p. 497-507
    Abstract: A novel small-molecule anthraquinone (AQ) analogue, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101–induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype and MDM2 expression in vitro and in vivo. When given for a period of 2 weeks (20 mg/kg/day, 3×/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2. Mol Cancer Ther; 17(2); 497–507. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-17-0566
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Abstract 3154: Translation of TRAF1 is regulated by IRES-dependent mechanism and stimulated by vincristine in lymphoid malignancies
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3154-3154
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3154-3154
    Abstract: TRAF1 is a member of the TRAF family, which plays important roles in signal transduction that mediate cell life and death in the immune response, inflammatory and malignant diseases. It is known that TRAF1 transcription is inducible by various cytokines, but little is known about the regulation of its protein translation. In the present study, we demonstrated that the human TRAF1 mRNA has an unusually long 5’-UTR that contains an IRES regulating TRAF1 protein translation. By performing gene transfection and reporter assays, we revealed that this IRES sequence is located within the 572 nucleotides upstream from the AUG start codon. An element between nucleotides −392 to −322 was essential for the IRES activity. Interestingly, we found that the TRAF1 expression is induced in cancer cells by chemotherapeutic drug vincristine that regulates cytoplasmic localization of PTB protein, which may contribute to the IRES-dependent translation of TRAF1 during vincristine treatment. These results indicate that TRAF1 translation is initiated via the IRES and regulated by vincristine, and suggest that regulation of the IRES-dependent translation of TRAF1 may be involved in effecting the cancer cell response to vincristine treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3154.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3154
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
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    Abstract 470: A MDM2 degrader inhibits cell proliferation and growth of MDM2-overexpressing acute lymphoblastic leukemia in SCID mice
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 470-470
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 470-470
    Abstract: The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression mainly through inhibition of the tumor suppressor p53. Here, we report a novel small-molecule chemical compound (MX69-114b) that we identified to induce MDM2 protein degradation resulting in reactivation of p53 and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL). We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modification of MX69 and selected analog MX69-114b showing increased MDM2-targeting activity. MX69-114b exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC50 values of 0.08-0.14 µM, representing a & gt;80-100-fold increase in activity compared to MX69. MX69-114b also showed inhibitory effects on xenografted human MDM2-overexpressing ALL in SCID mice at a much lower dose than did MX69. Importantly, MX69-114b had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-114b is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory ALL. Citation Format: tao Liu, Lubing Gu, Anna Mui, Zhongzhi Wu, Wei Li, Muxiang Zhou. A MDM2 degrader inhibits cell proliferation and growth of MDM2-overexpressing acute lymphoblastic leukemia in SCID mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 470.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-470
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    Inhibition of the Akt/survivin pathway synergizes the antileukemia effect of nutlin-3 in acute lymphoblastic leukemia cells
    American Association for Cancer Research (AACR) ; 2008
    In:  Molecular Cancer Therapeutics Vol. 7, No. 5 ( 2008-05-01), p. 1101-1109
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 7, No. 5 ( 2008-05-01), p. 1101-1109
    Abstract: The phosphatidylinositol 3-kinase (PI3K)/Akt and p53 pathways play antiapoptotic and proapoptotic roles in cell death, respectively. Cancer cell growth and progression are associated with high levels of PI3K/Akt activation by loss of PTEN expression and the inactivation of p53 by MDM2 overexpression. We report that inhibition of PI3K/Akt, either by the PI3K inhibitor Ly294002 or by expression of PTEN, synergized the ability of the MDM2 antagonist nutlin-3 to induce apoptosis in acute lymphoblastic leukemia (ALL). We used a set of ALL cell lines with wild-type p53 and MDM2 overexpression, but different status of PTEN expression/PI3K/Akt activation, to test the ability of nutlin-3 to induce p53 and apoptosis. Nutlin-3 activated p53 in all the ALL cell lines; however, induction of apoptosis was dependent on PTEN status. Nutlin-3 induced potent apoptosis in cells with PTEN expression but not in those without PTEN, suggesting that PTEN/PI3K/Akt pathway may play a role in this process. Furthermore, nutlin-3 significantly down-regulated survivin expression in PTEN-positive cells but not in PTEN-negative cells. When these nutlin-3–resistant cells were either pretransfected with the PTEN gene or simultaneously treated with the PI3K inhibitor Ly294002, survivin was down-regulated and sensitivity to nutlin-3 was increased. Furthermore, direct silencing of survivin by small interfering RNA also increased the proapoptotic effect of nutlin-3 on the PTEN-negative, nutlin-3–resistant ALL cells. Our results suggest that Akt-mediated survivin up-regulation in PTEN-negative ALL cells may counteract the proapoptotic effect of nutlin-3, and indicate that a combination of MDM2 antagonist and PI3K/Akt inhibitor may be a promising approach for treating refractory ALL. [Mol Cancer Ther 2008;7(5):1101–9]
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-08-0179
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 2062135-8
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  • 7
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    Online Resource
    Abstract 3471: Mutual regulation of MDM4 and TOP2A in cancer cell proliferation
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3471-3471
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3471-3471
    Abstract: MDM4 and topoisomerase IIα (TOP2A) are important cancer-related factors. MDM4 acts as an oncoprotein promoting cancer progression by inhibiting tumor suppressor p53. As a DNA replication- and cell division-regulating enzyme, TOP2A is the main target of many anticancer therapy regimens, even though the exact role of TOP2A in cancer remains elusive. Herein we report that MDM4 and TOP2A bind to each other and are mutually upregulated at the post-translational level, leading to enhanced TOP2A catalytic activity, inhibition of p53, and increased tumor-cell proliferation. We demonstrate that the C-terminal region (CTR) of TOP2A binds to a unique sequence (residues 188-238) of MDM4, which contains an auto-inhibitory segment regulating MDM4-p53 interaction. TOP2A binding in turn activates MDM4 for p53 binding, resulting in enhanced inhibition of p53 and cancer cell proliferation. Conversely, binding of the MDM4 sequence to the CTR of TOP2A upregulates TOP2A protein expression. This in turn interferes with TOP2A DNA-decatenating activity. These results reveal novel functions of MDM4 and TOP2A as well as their interactions in oncogenesis, suggesting that inhibition of the MDM4-TOP2A interaction may represent a novel strategy in specifically and simultaneously targeting TOP2A and MDM4 for cancer treatment. Citation Format: Tao Liu, Hailong Zhang, Sha Yi, Lubing Gu, Muxiang Zhou. Mutual regulation of MDM4 and TOP2A in cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3471.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3471
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Abstract 1202: MDM2 and its interaction with MYCN in neuroblastoma survival
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 1202-1202
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 1202-1202
    Abstract: The multifunctional oncoprotein MDM2 plays both p53-dependent and p53-independent roles in cancer initiation, progression and the development of resistance to therapy. Using a siRNA strategy to silence MDM2, which is highly expressed in neuroblastoma, we discovered that MDM2 regulates tumor cell growth and survival through distinct mechanisms in MYCN-amplified and non-MYCN-amplified neuroblastomas. MDM2 inhibition in a MDM2-overexpressing/non-MYCN-amplifying neuroblastoma cell line, SH-EP1, resulted in p53 activation, growth inhibition and apoptosis. In contrast, MDM2 inhibition in the MDM2-overexpressing/MYCN-amplifying neuroblastoma cell lines NB-1691 and IMR32 did not activate p53, despite expression of wild-type p53 in these lines. However, the siRNA silencing of MDM2 in NB-1691 and IMR32 cells did lead to complete inhibition of cell proliferation. In examining MYCN expression in these MYCN-amplified cells, we found that inhibition of MDM2 significantly downregulated MYCN expression at both the mRNA and protein levels. In a p53-null/MYCN-amplifying neuroblastoma cell line, LA1-55N, inhibition of MDM2 also decreased MYCN expression, inhibiting cell growth and apoptosis. These results suggest that MDM2 plays a p53-independent role in MYCN-amplified neuroblastomas. A critical factor for disease progression, we believe deregulation of MYCN expression may contribute significantly to the oncogenic properties of MDM2 in neuroblastoma. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1202.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-1202
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Online Resource
    Degradation of MDM2 by the Interaction between Berberine and DAXX Leads to Potent Apoptosis in MDM2-Overexpressing Cancer Cells
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 23 ( 2010-12-01), p. 9895-9904
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 23 ( 2010-12-01), p. 9895-9904
    Abstract: Berberine, a natural product derived from a plant used in Chinese herbal medicine, is reported to exhibit anticancer effects; however, its mechanism of action is not clearly defined. Herein, we demonstrate that berberine induces apoptosis in acute lymphoblastic leukemia (ALL) cells by downregulating the MDM2 oncoprotein. The proapoptotic effects of berberine were closely associated with both the MDM2 expression levels and p53 status of a set of ALL cell lines. The most potent apoptosis was induced by berberine in ALL cells with both MDM2 overexpression and a wild-type (wt)-p53, whereas no proapoptotic effect was detected in ALL cells that were negative for MDM2 and wt-p53. In contrast to the conventional chemotherapeutic drug doxorubicin, which induces p53 activation and a subsequent upregulation of MDM2, berberine strongly induced persistent downregulation of MDM2 followed by a steady-state activation of p53. We discovered that downregulation of MDM2 in ALL cells by berberine occurred at a posttranslational level through modulation of death domain-associated protein (DAXX), which disrupted the MDM2–DAXX–HAUSP interactions and thereby promoted MDM2 self-ubiquitination and degradation. Given that MDM2-overexpressing cancer cells are commonly chemoresistant, our findings suggest that this naturally derived agent may have a highly useful role in the treatment of cancer patients with refractory disease. Cancer Res; 70(23); 9895–904. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-1546
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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