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Human breast cancer cells display different sensitivities to ABT-263 based on the level of survivin
Lee, Eun Young,Gong, Eun-Yeung,Shin, Jae-Sik,Moon, Jai-Hee,Shim, Hyun Jae,Kim, Seung-Mi,Lee, Seul,Jeong, Joonyee,Gong, Ji Hee,Kim, Mi Jin,Lee, Dae Hee,Park, Yoon Sun,Shin, Jimin,Hong, Seung-Woo,Kim, Y Elsevier 2018 Toxicology in vitro Vol.46 No.-
<P><B>Abstract</B></P> <P>ABT-263 (navitoclax), a Bcl-2 family protein inhibitor, was clinically tested as an anti-cancer agent. However, the clinical trials were limited given the occurrence of resistance to monotherapy in breast cancer cells. Our study investigates the mechanisms for overcoming navitoclax resistance by combining it with an mTOR inhibitor to indirectly target survivin. The apoptotic effects of navitoclax occurred in MDA-MB-231 breast cancer cells in a time- and dose-dependent fashion, but MCF-7 cells were resistant to navitoclax treatment. The expression of Bcl-2 family genes was not altered by navitoclax, but the expression of survivin, a member of the inhibitors of apoptosis proteins (IAP) family, was downregulated, which increased death signaling in MDA-MB-231 cells. In MCF-7 cells, a navitoclax-resistant cell line, combined treatment with navitoclax and everolimus synergistically reduced survivin expression and induced cell death. These data indicate that navitoclax induces cell death in MDA-MB-231 cells but not in MCF-7 cells. Decreased survivin expression in MDA-MB-231 cells may be a primary pathway for death signaling. Combined navitoclax and everolimus treatment induces cell death by reducing the stability of survivin in MCF-7 cells. Given that survivin-targeted therapy overcomes resistance to navitoclax, this strategy could be used to treat breast cancer patients.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MDA-MB-231 and MCF-7 cell lines exhibit differential sensitivity to navitoclax induced apoptosis. </LI> <LI> Navitoclax-induced apoptotic cell death occurs through the regulation of survivin. </LI> <LI> Reduced expression levels of survivin restore navitoclax sensitivity in MCF-7 cell lines. </LI> <LI> Combined treatments with navitoclax and everolimus induces cell death in MCF-7 cells. </LI> </UL> </P>
Qamar, Imteyaz,Park, Eunsook,Gong, Eun-Yeung,Lee, Hyun Joo,Lee, Keesook American Society for Biochemistry and Molecular Bi 2009 The Journal of biological chemistry Vol.284 No.27
<P>ARR19 (androgen receptor corepressor of 19 kDa), which encodes for a leucine-rich protein, is expressed abundantly in the testis. Further analyses revealed that ARR19 was expressed in Leydig cells, and its expression was differentially regulated during Leydig cell development. Adenovirus-mediated overexpression of ARR19 in Leydig cells inhibited testicular steroidogenesis, down-regulating the expression of steroidogenic enzymes, which suggests that ARR19 is an antisteroidogenic factor. Interestingly, cAMP/luteinizing hormone attenuated ARR19 expression in a fashion similar to that of GATA-1, which was previously reported to be down-regulated by cAMP. Sequence analysis of the Arr19 promoter revealed the presence of two putative GATA-1 binding motifs. Further analyses with 5' deletion and point mutants of putative GATA-1 binding motifs showed that these GATA-1 binding sites were critical for high promoter activity. CREB-binding protein coactivated GATA-1 and markedly increased the activity of the Arr19 promoter. Both GATA-1 and CREB-binding proteins occupied the GATA-1 motifs within the Arr19 promoter, which was repressed by cAMP treatment. Altogether, these findings demonstrate that ARR19 is the target gene of GATA-1 and suggest that ARR19 gene expression in testicular Leydig cells is regulated by luteinizing hormone/cAMP signaling via the control of GATA-1 expression, resulting in the control of testicular steroidogenesis.</P>
Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist
Song, Chin-Hee,Yang, Su Hui,Park, Eunsook,Cho, Suk Hee,Gong, Eun-Yeung,Khadka, Daulat Bikram,Cho, Won-Jea,Lee, Keesook American Society for Biochemistry and Molecular Bi 2012 The Journal of biological chemistry Vol.287 No.36
Yang, Su Hui,Song, Chin-Hee,Van, Hue Thi My,Park, Eunsook,Khadka, Daulat Bikram,Gong, Eun-Yeung,Lee, Keesook,Cho, Won-Jea American Chemical Society 2013 Journal of medicinal chemistry Vol.56 No.8
<P>Molecular knowledge of pure antagonism and systematic SAR study offered a direction for structural optimization of DIMN to provide nicotinamides as a novel series of AR antagonists. Nicotinamides with extended linear scaffold bearing sterically bulky alkoxy groups on isoquinoline end were synthesized for H12 displacement. AR binding affinity and molecular basis of antiandrogenic effect establish the optimized derivatives, <B>7au</B> and <B>7bb</B>, as promising candidates of second generation AR antagonists for advanced prostate cancer.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2013/jmcmar.2013.56.issue-8/jm3014103/production/images/medium/jm-2012-014103_0011.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm3014103'>ACS Electronic Supporting Info</A></P>