bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 849: Autophagic cell death response to benzyl isothiocyanate exposure in human breast cancer cells is mediated by FoxO1
Authors: Xiao Dong , Bommareddy Ajay , Singh Shivendra V. 
Published: June 2012

Abstract
Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables (e.g., gardencress), is empowered to prevent chemically-induced cancers as well as oncogene-driven spontaneous mammary cancer development in rodent models. Furthermore, BITC treatment effectively inhibits growth of cultured as well as xenografted human breast cancer cells. However, the mechanisms underlying cancer chemopreventive responses to BITC are not fully understood. We now demonstrate, for the first time, that BITC causes FoxO1-mediated autophagic cell death in human breast cancer cells. Exposure of MDA-MB-231 (an estrogen-independent cell line with mutant p53) and MCF-7 (an estrogen-receptor positive cell line with wild-type p53) human breast cancer cells to BITC resulted in autophagy characterized by appearance of double-membrane structures judged by transmission electron microscopy, formation of acidic vesicular organelles evidenced by microscopy following staining with lysosomotropic agent acridine orange, cleavage of LC3 evidenced by immunoblotting, and punctuate localization of LC3. Interestingly, a spontaneously immortalized and non-tumorigenic human mammary epithelial cell line (MCF-10A) was resistant to autophagy induction by BITC. BITC-mediated growth inhibition and apoptotic cell death resulting from 6 hour treatment was significantly attenuated in the presence of autophagy inhibitor 3-methyladenineand (3-MA; a phosphatidylinositol 3-phosphate kinase inhibitor) and bafilomycin A1 (an inhibitor of vacuolar type H+-ATPase). On the other hand, growth inhibition and apoptotic DNA fragmentation resulting from 24 hour exposure to BITC was not prevented by either 3-MA or bafilomycin A. Furthermore, inhibition of MDA-MB-231 xenograft growth in female athymic mice by BITC administration (2.5 and 7.5 µmol BITC/mouse by i.p. injection) correlated with cleavage of LC3. BITC-induced autophagy was accompanied by induction of FoxO1. Moreover, RNA interference of FoxO1 conferred significant protection against BITC-mediated growth inhibition and autophagy. In conclusion, these results indicate that autophagy is an early event in growth inhibition by BITC against human breast cancer cells, which culminates into apoptotic cell death following longer exposures (e.g., 24 hours). This investigation was supported by the USPHS grant RO1 CA129347-04, awarded by the National Cancer Institute.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 849. doi:10.1158/1538-7445.AM2011-849
Abstract 852: Apoptosis induction by ayurvedic medicine constituent withaferin A in human breast cancer cells is mediated by reactive oxygen species-dependent activation of Bak
Authors: Hahm Eun-Ryeong , Moura Michelle B. , Kelley Eric E. , van Houten Bennett , Singh Shivendra V. 
Published: June 2012

Abstract
Withaferin A (WA) is a promising cancer chemopreventive constituent of Ayurvedic medicine plant Withania somnifera that has been used safely for thousands of years in India for treatment of different ailments. We have shown previously that WA treatment suppresses viability of cultured as well as xenografted human breast cancer cells by causing apoptosis but the mechanism of cell death is not fully understood. Here, we demonstrate that the WA-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species (ROS)-dependent activation of Bak. WA treatment caused ROS production in MDA-MB-231 (an estrogen-independent cell line with mutant p53) and MCF-7 cells (an estrogen-responsive cell line with wild-type p53) in a concentration- and time-dependent manner as judged by flow cytometry and fluorescence microscopy using a chemical probe (MitoSOX Red) and EPR spectroscopy using a cell permeable spin probe (1-hydroxy-3-methoxy-carbonyl-2,2,5,5-tetramethylpyrrolidine). WA-mediated ROS production, as well as, apoptosis [characterized by release of histone-associated DNA fragments into the cytosol, and cleavage of poly-(ADP-ribose) polymerase or procaspase-3], was significantly attenuated by ectopic expression of Cu,Zn-superoxide dismutase (SOD) or Mn-SOD. Real-time measurements of oxygen consumption rate and extracellular acidification rate using a Seahorse Bioscience XF24 Extracellular Flux Analyzer revealed that the ROS production resulting from WA exposure was accompanied by inhibition of basal and reserve oxidative phosphorylation. Mitochondrial DNA-deficient Rho-0 variants of MDA-MB-231 and MCF-7 cells were significantly more resistant to WA-induced ROS production and apoptosis compared with respective wild-type cells. WA treatment resulted in activation of Bax and Bak, but only Bak activation was attenuated by Cu,Zn-SOD overexpression. Furthermore, RNA interference or genetic suppression of Bax and Bak expression conferred significant protection against WA-induced apoptosis. In conclusion, the present study provides novel insights into the molecular circuitry of WA-induced apoptosis involving ROS-dependent activation of Bak. This investigation was supported by the USPHS grant CA142604-01, awarded by the National Cancer Institute.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 852. doi:10.1158/1538-7445.AM2011-852
Abstract 858: Transplacental cancer prevention by indole-3-carbinol via estrogen receptor beta
Authors: Benninghoff Abby D. , Fish Trevor , Packard Brittany C. , Castro David J. , Shorey Lyndsey E. , Williams David E. 
Published: June 2012

Abstract
Indole-3-carbinol (I3C), a key active component of cruciferous vegetables, was recently shown to be an effective anticancer agent when administered transplacentally to mice via the maternal diet. The chemopreventive properties of I3C can involve multiple mechanisms of action, including interaction with the aryl hydrocarbon receptor (AhR) and the estrogen receptor (ER). In this prior transplacental cancer study, the chemopreventive property of I3C was not dependent on the AhR. In the present study, the therapeutic efficacy of I3C in prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[a,l]pyrene (DBP) was evaluated using an ER beta knockout mouse model. B6129SF1/J-Esr2+/- dams and sires were crossed to generate offspring that were either wild-type, heterozygous or null for ER beta. Dams were initiated with 15 mg/kg DBP or sham (corn oil) on gestation day 17. Three experimental diets were evaluated as follows: group 1, dams and offspring were fed control diet throughout the study; group 2, dams were fed 2000 ppm I3C from gestation day 9 through lactation (I3C-GL); and group 3, offspring were fed 2000 ppm I3C from weaning until 6 months of age (I3C-PW). As previously observed, offspring in the DBP-initiated control group developed T-cell lymphoblastic lymphoma by 20 weeks of age, whereas mice in the I3C-GL group were less likely to succumb to the disease (p&lt;0.0001). Although I3C did not reduce incidence of lung cancer in the surviving offspring, lung tumor multiplicity in mice exposed to I3C during gestation and lactation (I3C-GL) was significantly reduced compared to control (p&lt;0.05). I3C administered directly to the offspring (I3C-PW) did not provide protection against DBP-dependent lymphoma or reduce lung tumor multiplicity. This observation points to the critical gestation/lactation window of exposure for chemoprevention by this compound. A significant effect of ER beta genotype was observed in offspring exposed to I3C during gestation and lactation, only. Lymphoma-related mortality was very low in offspring expressing one or both copies of ER beta (+/-, 89% survival; +/+, 96% survival), whereas mortality in offspring lacking ER beta was significantly higher (−/-, 58% survival; p=0.0001.) Interestingly, in this diet group, lung tumor multiplicity in ER beta null offspring was significantly lower than wild-type or heterozygous mice. Collectively, these findings suggest that I3C acts via ER beta to exert its anticancer effects when administered transplacentally to offspring via the maternal diet. Supported by grants F32ES014777, P01CA090890 and the Linus Pauling Institute.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 858. doi:10.1158/1538-7445.AM2011-858
Abstract 859: EGCG inhibits pancreatic cancer growth and stem cell characteristics in xenografts and KrasG12D transgenic mice models
Authors: Tang Su-Ni , Marsh Luke , Shankar Sharmila , Srivastava Rakesh K. 
Published: June 2012

Abstract
FoxO (forkhead box O) transcription factors are crucial regulators of cell fate. This function of FoxO proteins relies on their ability to control diverse functions such as proliferation, differentiation, DNA repair and apoptosis. Constitutively active AKT and ERK in cancer cells have been shown to phosphorylate FoxO transcription factors (FKHR, FKHRL1 and AFX), which bind to protein 14-3-3 and sequester in the cytoplasm. In the absence of survival signals, FoxO proteins dephosphorylate, translocate to the nucleus and upregulate a series of target genes, thereby promoting cell cycle arrest and apoptosis. EGCG, a component of green tea, exerts antiproliferative and proapoptotic actions on a number of different cancer cell lines through diverse mechanisms. However, the mechanisms by which EGCG inhibits cell proliferation and induces apoptosis are poorly understood. EGCG inhibited viability and induced apoptosis in human pancreatic cancer cell lines. EGCG induces PTEN expression and inhibits Akt phosphorylation in pancreatic cancer Hs766T, AsPC-1, MIA PaCa-2 and PANC-1 cells. Treatment of PANC-1 cells with EGCG caused a decrease in ERK phosphorylation, and an increase in JNK phosphorylation. Overexpression of FOXO1, FOXO3a, and FOXO4 inhibited cell viability in PANC-1 cells. The inhibitory effects of EGCG on cell viability were further enhanced when cells were transfected with FOXO1, FOXO3a, and FOXO4. EGCG enhanced FOXO-DNA binding and transcriptional activities. Interestingly, EGCG inhibited pancreatic cancer growth and/or development in xenograft, orthotopic and KrasG12D transgenic mice models. EGCG also inhibited pancreatic cancer stem cell characteristics. In conclusion, our data demonstrate that EGCG can inhibit pancreatic cancer growth and/or development through multiple mechanisms and thus can be used for the management of pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 859. doi:10.1158/1538-7445.AM2011-859
Abstract 861: Nrf2-mediated induction of heme oxygenase-1 expression by cyclopentenone prostaglandin analogues in human breast epithelial cells: Structure-activity relationships
Authors: Park Jong-Min , Kim Nam-Jung , Na Hye-Kyung , Suh Young-Ger , Surh Young-Joon 
Published: June 2012

Abstract
15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been known to induce heme oxygenase-1 (HO-1) in certain cell lines. The mechanism by which 15d-PGJ2 upregulates HO-1 expression is considered to involve covalent modifications of critical cysteine residues of Keap1, a cytoplasmic repressor of Nrf2. This facilitates dissociation of Nrf2 from Keap1 for nuclear translocation and binding to the antioxidant response element. In the present work, we synthesized a series of 15d-PGJ2 analogues: i) Halogenated 15d-PGJ2 derivatives by introducing an electron withdrawing group, i.e., halogen into the electrophilic carbon; ii) Olefin modified 15d-PGJ2 analogues by saturating an electrophilic α,β-unsaturated carbonyl moiety in the cyclopentenone ring; iii) Combined halogenated and olefin modified 15d-PGJ2 analogues with more potent electrophilic nature to form stable Keap1 adducts. Twelve 15d-PGJ2 analogues were synthesized that retain the essential structural features of 15d-PGJ2 with different capabilities to induce Nrf2 activation. When treated to the human breast epithelial cell line (MCF10A), halogenated 15d-PGJ2 analogues were found to have high potency and efficacy for inducing HO-1 expression as well as Nrf2 activation (-Cl &gt; -Br &gt; -F = -I). 14,15-Dihydro-PGJ2 also retains capability to induce HO-1 expression and Nrf2 activation. However, abilities of both 9,10-dihydro-15d-PGJ2 and 12,13-14,15-tetrahydro-PGJ2 to induce HO-1 expression and Nrf2 activation were abolished due to lack of the electrophilic α,β-unsaturated carbonyl moiety. Chlorinated 14,15-dihydro-PGJ2 has the highest potency and efficacy for HO-1 induction via Nrf2 activation. We further showed that biotinylated 15d-PGJ2 directly bound to Keap1, which was confirmed by avidin pull-down. Biotinylated chloro 14,15-dihydro-PGJ2 interacted with Keap1 to a greater extent than did 15d-PGJ2. In contrast to 15d-PGJ2, 9,10-dihydro-15d-PGJ2 failed to modify Keap1. Taken together, these results suggest that 15d-PGJ2 containing an electrophilic cyclopentenone moiety can directly modify Keap1, presumably at its critical cysteine residue. As halogenated 15d-PGJ2 analogues and 14,15-dihydro-PGJ2 can stably interact with Keap1, they can be utilized as lead compounds for the development of anti-inflammatory and chemopreventive agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2011-861
Abstract 864: Benzyl isothiocyanate, a promising cancer chemopreventive constituent of cruciferous vegetables, inhibits epithelial to mesenchymal transition in human breast cancer cells in vitro and in vivo
Authors: Sehrawat Anuradha , Singh Shivendra V. 
Published: June 2012

Abstract
Benzyl isothiocyanate (BITC), a constituent of cruciferous vegetables (e.g., garden cress), inhibits chemically-induced cancer in experimental rodents. We showed previously that BITC treatment inhibited growth of cultured (MDA-MB-231 and MCF-7) and xenografted (MDA-MB-231) human breast cancer cells by causing reactive oxygen species-dependent apoptosis, and suppressed mammary cancer development in a transgenic mouse model (MMTV-neu). We now demonstrate, for the first time, that BITC is a potent inhibitor of epithelial to mesenchymal transition (EMT) in cultured cells and tumor xenografts in vivo. Exposure of estrogen receptor negative (MDA-MB-231) and estrogen receptor positive human breast cancer cells (MCF-7) and a highly invasive pancreatic cancer cell line (PL-45) to pharmacologic concentrations of BITC (1 or 2.5 µmol/L) resulted in up-regulation of epithelial markers (e.g., E-cadherin and occludin) with a concomitant decline in protein levels of mesenchymal markers vimentin, fibronectin, snail, and/or c-Met. BITC-mediated induction of E-cadherin protein correlated with its transcriptional up-regulation. Experimental EMT induced by exposure to TGFβ and TNFα in a spontaneously immortalized and non-tumorigenic human mammary epithelial cell line (MCF-10A) was also largely reversible in the presence of BITC. Consistent with these results, the BITC treatment inhibited TGFβ/TNFα -induced migration by MCF-10A cells, which was partially but significantly attenuated by RNA interference of E-cadherin. Moreover, inhibition of MDA-MB-231 xenograft growth in vivo in female athymic mice by BITC administration correlated with a visible increase in protein level of E-cadherin and suppression of vimentin protein expression. In conclusion, the present study reports a novel anticancer effect of BITC involving inhibition of EMT, a process triggered during progression of carcinoma to invasive state. This investigation was supported by the USPHS grant RO1 CA129347-04, awarded by the National Cancer Institute.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 864. doi:10.1158/1538-7445.AM2011-864
Abstract 868: Replication of melanoma GWAS hits and exploration of pleiotropic effects of cancer GWAS hits with melanoma risk in the PAGE study
Authors: Kocarnik Jonathan D. , Carty Cara , Lin Yi , Fesinmeyer Megan D. , Haessler Jeff , Kooperberg Charles , Peters Ulrike ,   PAGE Consortium
Published: June 2012

Abstract
Introduction: As the most serious form of skin cancer, melanoma is a considerable public health burden. Genome wide association studies (GWAS) have successfully identified several loci important to melanoma susceptibility. Some of these loci have been associated with other cancers as well, similar to the pleiotropy previously demonstrated in the 8q24 and TERT regions. Such pleiotropy can highlight important regions and may help inform variant functionality. However, the potential pleiotropic effects of gene variants identified for other cancers have not been fully explored for melanoma. This study evaluates whether GWAS hits for melanoma, as well as hits for non-melanoma cancers, are associated with melanoma risk.
Methods: We included 918 white melanoma cases and 4495 white controls in the Women's Health Initiative, which were genotyped as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. We evaluated 8 single nucleotide polymorphisms (SNPs) previously shown to be associated with melanoma in GWAS as well as 175 SNPs previously shown to be associated with other cancers. These findings were mostly based on GWAS in Caucasian populations. We used logistic regression to evaluate the association between each SNP and melanoma risk, using an age-adjusted additive genetic model.
Results: Of the 8 melanoma SNPs evaluated, 7 were statistically significantly associated with melanoma risk (p&lt;0.05). These SNPs were rs1393350 (p=0.001), rs16891982 (p=3.34e-05), rs258322 (p=1.53e-9), rs4785763 (p=3.29e-4), rs7023329 (p=2.20e-5), rs910873 (p=2.38e-4), and rs4636294 (p=5.82e-5). For each of these significant SNPs, the association was in the same direction of risk as previously reported. The SNP that did not replicate was rs2284063 (p=0.38). Our analysis for pleotropic effects of other cancer GWAS hits did not yield any significant associations after adjustment for multiple comparisons (p=2.87e-4). The most significant SNP was rs710521 (p=0.006), previously associated with urinary bladder cancer.
Conclusions: This preliminary analysis demonstrates that nearly all previously discovered melanoma SNPs replicated. Our analysis did not discover any non-melanoma cancer SNPs that are also associated with melanoma. The next step in this analysis will be to incorporate data from the other three PAGE studies: the Multiethnic Cohort (MEC), Epidemiologic Architecture of Genes Linked to Environment (EAGLE), and the CALiCo Consortium (see pagestudy.org). This will substantially improve the power of our pleiotropy analyses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 868. doi:10.1158/1538-7445.AM2011-868
Abstract 879: A functional promoter polymorphism (−1362G&gt;T) of IL-6 gene is associated with the risk of squamous cell carcinoma of head and neck
Authors: Huang Yu-Jing , Niu Jiangong , Wang Li-E , Liu Zhensheng , Sturgis Erich M. , Wei Qingyi 
Published: June 2012

Abstract
Interleukin-6, an immunoregulatory cytokine, plays a crucial role in the pathogenesis of a wide variety of human cancers, and the IL-6 levels have been shown to be associated with tumor progression in human squamous cell carcinoma of the head and neck (SCCHN). Because the presence of polymorphisms in the non-coding gene regulatory region may affect transcriptional regulation of IL-6, we hypothesized that such genetic variants of IL-6 might contribute to susceptibility to SCCHN. To assess the association between IL-6 polymorphisms and SCCHN risk, two independent IL-6 promoter SNPs, -1362 G&gt;T (rs2069827) and -597 G&gt;A (rs1800797), the latter being in nearly complete linkage disequilibrium with -173 C&gt;G (rs1800795), were genotyped in 1,092 non-Hispanic White SCCHN patients and 1,126 age-and sex-matched cancer-free controls. After adjustment for age, sex, and smoking and drinking status, a significantly higher risk was observed for the -1362GT+TT genotypes (adjusted OR = 1.28, 95% CI = 1.01-1.62), compared with those carrying the -1362GG homozygotes, but not for the -597G&gt;A SNP. Additional functional experiment demonstrated that the IL-6 SNP -1362 G-to-T allelic change was associated with an increased promoter activity in human head and neck cell lines, supporting the hypothesis that genetic polymorphism influencing IL-6 transcription may play a role in human SCCHN carcinogenesis. We conclude that the IL-6 promoter -1362 G&gt;T (rs2069827) polymorphism is functional, modulating susceptibility to SCCHN among non-Hispanic Whites. Larger studies are needed to validate our findings. (Supported by NIH grants R01CA131274, R01ES011740 and P30 CA016672)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 879. doi:10.1158/1538-7445.AM2011-879