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  • American Association for Cancer Research (AACR)  (3)
  • 1
    Online Resource
    Online Resource
    BRCA1 Induces Antioxidant Gene Expression and Resistance to Oxidative Stress
    American Association for Cancer Research (AACR) ; 2004
    In:  Cancer Research Vol. 64, No. 21 ( 2004-11-01), p. 7893-7909
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 64, No. 21 ( 2004-11-01), p. 7893-7909
    Abstract: Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor, confer an increased risk for breast, ovarian, and prostate cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to identify BRCA1-regulated gene expression changes. We found that BRCA1 up-regulates the expression of multiple genes involved in the cytoprotective antioxidant response, including glutathione S-transferases, oxidoreductases, and other antioxidant genes. Consistent with these findings, BRCA1 overexpression conferred resistance while BRCA1 deficiency conferred sensitivity to several different oxidizing agents (hydrogen peroxide and paraquat). In addition, in the setting of oxidative stress (due to hydrogen peroxide), BRCA1 shifted the cellular redox balance to a higher ratio of reduced to oxidized glutathione. Finally, BRCA1 stimulated antioxidant response element-driven transcriptional activity and enhanced the activity of the antioxidant response transcription factor nuclear factor erythroid-derived 2 like 2 [also called NRF2 (NFE2L2)]. The ability of BRCA1 to stimulate antioxidant response element-dependent transcription and to protect cells against oxidative stress was attenuated by inhibition of nuclear factor erythroid-derived 2 like 2. These findings suggest a novel function for BRCA1, i.e., to protect cells against oxidative stress. This function would be consistent with the postulated role of BRCA1 as a caretaker gene in preserving genomic integrity.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-04-1119
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 3409: Inhibition of checkpoint kinase 2 enhances sensitivity of pancreatic adenocarcinoma cells to Gemcitabine.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3409-3409
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3409-3409
    Abstract: Checkpoint kinase 1/2 (Chk1/2) plays pivotal function as effectors of cell cycle checkpoint regulation following DNA damage. Small molecule inhibitors of Chk1/2 are under clinical evaluation in combination with chemotherapeutic agents. We examined whether NSC109555, a competitive inhibitor of Chk2 inhibitor could enhance the synergistic antitumor effect(s) of Gemcitabine(GEM) in pancreatic adenocarcinoma cell model. In the present study, the combination treatment by NSC109555 plus GEM demonstrated strong synergistic antitumor effect in four pancreatic cancer cells. In addition, the combination treatment of NSC109555 plus GEM significantly increased the generation of intracellular reactive oxygen species (ROS), followed by induction of apoptotic cell death. Furthermore, the inhibition of ROS generation by N-acetyl cysteine (NAC) significantly prevented the decrease in cell survival and increase in apoptotic cell death by combination treatment of NSC109555 plus GEM. Small interfering RNA (siRNA) mediated knockdown of Chk2 also enhanced GEM-inhibited cell survival and GEM-induced apoptotic cell death. Our findings suggest that NSC109555 would be beneficial therapeutic agents when combined with GEM and support the novel synthetical lethal approach for cancer therapy by these combinations for preclinical and clinical treatment of pancreatic cancer. Citation Format: Hong-Quan Duong, Jung Soon Kim, Hee-Seok Lee, Yeon-Sun Seong, Insoo Bae, Dept. Oncol and Dept. of Rad. Medicine, Lombardi Comprehensive Cancer Center, Georgetown University. Inhibition of checkpoint kinase 2 enhances sensitivity of pancreatic adenocarcinoma cells to Gemcitabine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3409. doi:10.1158/1538-7445.AM2013-3409
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3409
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract 4976: Crif1, a new negative regulator of Nrf2
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4976-4976
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4976-4976
    Abstract: Abstract Free radicals generated by oxidative stress cause damage that can contribute to numerous chronic diseases. Mammalian cells respond to this damage by increased transcription of cytoprotective phase II genes, which are regulated by Nrf2. Previously, it has been shown that Nrf2 protein levels increase after oxidative stress because its negative regulator, Keap1, loses its ability to bind Nrf2 and cause its proteasomal-mediated degradation during oxidative stress. Here, we show that Crif1 is also able to negatively regulate Nrf2 protein stability. However, and in contrast to Keap1, which regulates Nrf2 stability only under normal reducing conditions, Crif1 regulates Nrf2 stability, accumulation and target gene expression under both reducing and oxidative stress conditions. Thus, Crif1-Nrf2 interactions and their consequences are redox-independent. In addition, Crif1, but not Keap1 (which only interacts with N-terminal region of Nrf2), physically interacts with both N- and C-terminal regions of Nrf2 and promote Nrf2 ubiquitination and proteasomal-mediated degradation. Finally, Crif1 can modulate cells’ sensitivity to oxidative stress-induced cytotoxicity. 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 4976.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-4976
    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
    Location Call Number Limitation Availability
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