bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5547: Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis
Authors: Singhal Sharad S. , Yadav Sushma , Wickramachchi Dilki , Singhal Jyotsana , Leake Kathryn , Vatsyayan Rit , Chaudhary Pankaj , Awasthi Yogesh , Awasthi Sanjay 
Published: June 2012

Abstract
Targeted depletion of the RALBP1 encoded 76 kDa splice variant, RLIP76, causes marked and sustained regression of human xenografts of lung, colon, prostate, and kidney cancer without toxicity in nude mouse models. We proposed that the remarkable efficacy and broad-spectrum of RLIP76-targeted therapy is because its glutathione-conjugate (GS-E) transport-activity is required for clathrin-dependent endocytosis (CDE) that regulates all ligand-receptor signaling and that RLIP76 is required not only for survival of cancer cells, but also for their very existence. We studied RLIP76 mutant proteins and the functional consequences of their expression into RLIP76−/− MEFs which identified key residues for GS-E binding in RLIP76, established the requirement of RLIP76-mediated GS-E transport for CDE and demonstrated a direct correlation between GS-E transport activities with CDE. Depletion of RLIP76 near completely blocked signaling down-stream of EGF in a CDE-dependent manner and Wnt5a signaling in a CDE-independent manner. The seminal prediction of this hypothesis, that RLIP76−/− mice will be deficient in chemical neoplasia, was confirmed. Benzo[a]pyrene, dimethylbenzanthracene and phorbol esters are ineffective in causing neoplasia in RLIP76−/−. PMA-induced skin carcinogenesis in RLIP76+/+ mouse was suppressed completely by depletion of either PKCα or RLIP76 by siRNA or antisense and could be restored by topical application of RLIP76 protein in RLIP76−/− mouse skin. Likewise, chemical pulmonary carcinogenesis was absent in female and nearly absent in male RLIP76−/− mice. In RLIP76−/− mice, p53, p38, and JNK activation did not occur in response to either carcinogen. Our findings demonstrate a fundamental role of RLIP76 in chemical carcinogenesis. (Supported in part by NIH grant CA 77495 (SA), CA 155350, Cancer Research Foundation of North Texas, and Institute for Cancer Research & the Joe & Jessie Crump Fund for Medical Education (SS))
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 5547. doi:10.1158/1538-7445.AM2011-5547
Abstract 555: 3D tumor models for the assessment of molecular targeted therapies
Authors: Onion David , Argent Richard H. , Kumari Rajendra , Axel Amy , Hall Brett , Watson Susan A. 
Published: June 2012

Abstract
It is becoming increasingly apparent that the interaction between the tumor and the surrounding stromal cells is critical to tumor growth, invasion and metastasis. These paracrine interactions can profoundly alter EMT profiles and modulate key growth factor signaling cascades which can lead to altered responsiveness to molecular targeted therapies such as EGF-R TKI inhibitors. We have developed a novel 3D tumor growth assay, where the paracrine interaction between tumor derived fibroblasts and epithelial cells are restored. Utilizing luminescent and fluorescent labeled cell populations we are able to monitor tumor-microenvironment driven tumor growth in the presence of targeted therapies in comparison to standard platinum dublet therapies. Primary tumor associated fibroblasts and mesenchymal stem cells drive growth and proliferation of non-small cell lung cancer cell lines of adenocarcinoma (A549, NCI-H358, NCI-H460) and squamous subtypes (SK-MES1, H226) as well as early stage disease (NCI-H322M). The paracrine interaction promotes 3D structure formation and invasion into laminin rich basement membrane extract. Cells grown in 3D assays show a slowed proliferation and lower sensitivity to anti-mitotic agents such as paclitaxel. As proof of concept we show that responsiveness to EGF-R TKI is significantly decreased in the presence of HGF secreting stromal cells irrespective of EGF-R and KRAS mutational status. The 3D growth assay provides a more tumor microenvironment relevant model for pre-clinical testing of molecular targeted therapies.
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 555. doi:10.1158/1538-7445.AM2011-555
Abstract 5562: High-fat diet feeding increases tumor growth and metastasis of mammary carcinoma cells in the 4T1 orthotopic BALB/c mouse model
Authors: Kim Eun Ji , Choi Mi-Ran , Park Heesook , Kim Minhee , Hong Ji Eun , Lee Jae-Yong , Park Jung Han Yoon 
Published: June 2012

Abstract
We previously observed that chronic consumption of a high fat-diet (HFD) increased the breast cancer-related mortality in the 4T1 orthotopic mouse breast cancer model. In the present study, we determined whether feeding mice with a HFD for a prolonged period increases solid tumor growth and metastasis of breast cancer cells using the 4T1 orthotopic model. 4-week old, female BALB/c mice were fed a purified diet containing 60 kcal% fat (HFD) or 10 kcal% fat (control diet) for a period of 16 weeks. After 16 weeks, 4T1 mammary carcinoma cells (5 × 104 cells) were injected into the inguinal mammary fat pad of syngeneic female BALB/c mice and the mice were continuously fed the same diets. Solid tumor growth was increased in the HFD group as compared to the control diet group. Additionally, chronic consumption of the HFD markedly increased the number and volume of tumor nodules in the lung and liver. The expression of cyclin-dependent kinase (CDK)2, CDK4, cyclin D1, cyclin A, Ki67, vascular endothelial growth factor, CD31 (an angiogenesis marker), and CD45 (a monocyte/macrophage marker) was markedly increased in the tumor tissues in the HFD group as compared to control diet group. The protein levels of urokinase-type plasminogen activator (uPA), intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule-1 were significantly increased but those of plasminogen activator inhibitor-1 were decreased in the lung tissues of the HFD group as compared to control diet group. The serum levels of complement fragment 5a (C5a), interleukin (IL)-6, macrophage colony stimulating factor (M-CSF), soluble intercellular adhesion molecule (sICAM)-1, tissue inhibitors of metalloproteinase (TIMP)-1, and triggering receptor expressed on myeloid cells (TREM)-1 were up-regulated in the HFD group as compared to control diet group. We conducted in vitro assays to determine effect of these cytokines, which had been increased in the sera of mice fed on the HFD, on the cell proliferation, adhesion, and migration of 4T1 cells. sICAM-1 increased the viability of 4T1 cells. TREM-1, M-CSF, and sICAM-1 significantly increased the migration of 4T1 cells. Additionally, the capacity of 4T1 cells to adhere to strips coated with human collagen type I was increased by C5a, sICAM-1, IL-16, M-CSF, TIMP-1, and TREM-1. These results indicate that, in addition to adhesion molecules, metalloproteases and pro-angiogenic factors, the cytokines C5a, sICAM-1, IL-16, M-CSF, TIMP-1, and TREM-1 play important roles in the metastasis of mammary cancer cells in mice fed on a HFD for a prolonged period.
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 5562. doi:10.1158/1538-7445.AM2011-5562
Abstract 5576: Rhamnetin inhibits human prostate cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators and survival molecules
Authors: Shukla Sanjeev , Bhaskaran Natarajan , Gupta Sanjay 
Published: June 2012

Abstract
Development of effective agents for treatment of prostate cancer has become a national medical priority. Rhamnetin (3,5,3,4-tetrahydroxy-7-methoxyflavone), a natural compound known as O-methylated flavonol, abundantly present in cloves, sweet annie, annual wormwood, green vegetables and orchard grass has shown to possess anti-inflammatory and antioxidant properties. However, the anticancer properties of rhamnetin have not been fully elucidated. In the present study we demonstrated the molecular mechanism of cell growth inhibition and induction of apoptosis in human prostate carcinoma LNCaP and PC-3 cells by rhamnetin. Treatment of these cells with rhamnetin resulted in a dose (5, 10, 20, 40 microM) and time (24, 48 and 72 h) dependent inhibition of growth, G2-S phase arrest of the cell cycle and DNA fragmentation. This effect was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner, cyclin-dependent kinase (cdk) 2, 4, and 6, with concomitant upregulation of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18. Rhamnetin treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome-c and induction of apoptotic protease-activating factor-1 (Apaf-1). This effect was found to result in a significant increase in cleaved fragments of caspase-9, -3, and poly (ADP-ribose) polymerase (PARP). Further, rhamnetin treatment resulted in down modulation of XIAP, survivin, and c-Myc protein expressions. Taken together, we concluded that molecular mechanisms during rhamnetin-mediated growth inhibition and induction of apoptosis in both androgen-responsive, LNCaP and androgen-refractory, PC-3 cells was due to modulation in cell-cycle machinery, disruption of mitochondrial function, and inhibition of cell survival machinery. For the first time we provide evidence that rhamnetin acts on potential molecular targets of cell cycle regulation and survival to elicit anticancer effects in prostate cancer cells.
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 5576. doi:10.1158/1538-7445.AM2011-5576
Abstract 5580: Simvastatin induces expression of miRNA-200a and let-7c, leading to mRNA and protein expression of E-cadherin and reduced cell migration in PC-3 cells
Authors: Liu Shuman , Li Xuesen , Liu Zhongbo , Xu Xia , Blair Christopher , Simoneau Anne , Zi Xiaolin 
Published: June 2012

Abstract
Simvastatin is a widely used cholesterol-lowering drug. Emerging evidence suggests that statins including simvastatin have other biological effects linked to a reduced risk of prostate cancer recurrence. We have examined the effect of simvastatin on invasive capacity of PC-3 cells, a cell line derived from a prostate cancer bone metastasis specimen. Our results showed that simvastatin treatment of PC3 cells at concentrations of 0.5 and 1 μM for 8 hours significantly increased the expression of miRNA-200a and let-7c. miRNA-200a and let-7c have been reported to be involved in epithelial to mesenchymal transition (EMT). At the same concentrations, simvastatin significantly induced the protein and mRNA expression of E-cadherin, a hallmark for EMT. In addition, simvastatin treatment of PC-3 cells caused markedly increased activities of Rho GTPases including RhoA, Cdc42 and Rac1. Collectively, these molecular events caused by simvastatin led to a significant reduction of PC-3 cell migration in a wound-healing experiment. Therefore, simvastatin exhibits a novel anti-migration activity against metastatic prostate cancer, suggesting a potential role for simvastatin in prevention of prostate cancer recurrence after prostatectomy.
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 5580. doi:10.1158/1538-7445.AM2011-5580
Abstract 5581: Korean Angelica gigas Nakai (AGN) and Oriental herbal cocktail ka-mi-kae-kyuk-tang (KMKKT) inhibit prostate carcinogenesis in TRAMP model
Authors: Wang Lei , Zhang Yong , Zhang Jinhui , Nkata Katai , Quealy Emily , Li Li , Lee Hyo-Jeong , Jeong Soo-Jin , Liao Joshua , Jiang Cheng , Kim Sung-Hoon , Lu Junxuan 
Published: June 2012

Abstract
The ka-mi-kae-kyuk-tang (KMKKT) is a formula of ten Oriental herbs containing Korean Angelica gigas Nakai (AGN) root. Previous studies by our collaborative team found that the KMKKT ethanol extract exerted anti-angiogenesis, apoptosis and anti-metastasis in vitro and in vivo (carcinogenesis 2006). We also showed that AGN extract suppressed DU-145 & PC-3 xenograft growth (Am J Chin Med 1009).
In the present study, we used the transgenic adenocarcinoma of the mouse prostate (TRAMP) spontaneous primary carcinogenesis model to establish the chemoprevention efficacy of KMKKT and AGN and to explore cellular and molecular correlates of the in vivo anti-cancer effects. Male C57BL6 TRAMP mice were given a daily gavage (5 times per wk, 5 mg/mouse) as KMKKT and AGN beginning at 8 weeks of age (1% Tween-80 as vehicle n=13; KMKKT n=14; AGN n=17). We treated wild-type littermates also with KMKKT and AGN. All mice were terminated at 24 weeks of age, unless earlier euthanasia was necessitated by large tumor size.
The results show that the genitourinary (GU) tract weight was decreased in both KMKKT (66.4%) and AGN (57.6%) treated groups compared to vehicle group (100%). The dorsal-lateral prostate (DLP) weight was significantly lower in KMKKT and AGN groups compared to control group (P=0.02), with no difference found in the wild-type mice cohorts. In TRAMP and wild-type mice that received KMKKT and AGN vs. vehicle, there is no significant difference of the body weight and main organs (liver and kidney) (P&gt;0.05). Additionally, macroscopical prostate tumors were found 46.2% (6/13) in control group, but just 14.3% (2/14) and 17.6% (3/17) in KMKKT and AGN group (Chi-square analysis P=0.07 and P=0.09). The average tumor burden was 0.81g/mouse in control group, 0.27 and 0.12 g/mouse in KMKKT and AGN group, respectively. All these macroscopical tumors are T-antigen (+), synaptophysin(+), androgen-receptor(−) and E-cadherin(−) poorly differentiated neuro-endocrine carcinoma (NECa). Furthermore, KMKKT and AGN-treated NECa contained lower basic fibroblast growth factor (bFGF) detectable by WB, antibody array and IHC. Decursinol, the hydrolysis product of decursin and DA was detectable in the plasma of AGN-treated mice.
In summary, results from this pilot study indicate that oral administration of KMKKT and AGN may inhibit prostate primary carcinogenesis in the TRAMP model. Additional chemoprevention studies are merited. [Grant support: NCCAM 1R21AT005383, NCI R01CA136953, R01CA126880 and Korean KOSEF-MEST No. 2009-0063466].
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 5581. doi:10.1158/1538-7445.AM2011-5581
Abstract 5587: Bitter melon (Momordica charantia) extract suppresses adrenocortical cancer cell proliferation and growth through modulation of the cell cycle pathway and steroidogenic activity
Authors: Brennan Victoria C. , Wang Chiung-Min , Yang Wei-Hsiung 
Published: June 2012

Abstract
Malignant adrenal tumors or adrenocortical carcinomas are relatively rare; however, this form of cancer is highly malignant and presents with extremely poor prognosis as a consequence of metastasis or local invasion at the time of diagnosis. One of the approaches to control cancer progression and reduce cancer risk is prevention through diet. Bitter melon is widely consumed as a vegetable and especially as a traditional medicine in China, India, Japan, and Taiwan. In this study, we have used human and mouse adrenocortical cancer cells, H295R and Y1, respectively, as an in vitro model to assess the efficacy of bitter melon extract (BME) as an anticancer agent. First, we find that BME treatment of adrenocortical cancer cells results in a significant dose-dependent decrease in cell proliferation and growth. We also find that bitter melon extract has stronger anti-proliferation effect than blueberry extract on adrenocortical cancer cells. As expected, extracts from Acorn squash and Zucchini, two vegetables from the same Family of Cucurbitaceae as bitter melon, do not decrease cell proliferation in adrenocortical cancer cells. Second, apoptosis of adrenocortical cancer cells is accompanied by increased caspase activation and poly(ADP-ribose) polymerase cleavage. Further studies reveal that BME treatment enhances p53, p21, Mdm2, and ATF3 and inhibits cyclin D1, cyclin D2, cycline D3, mTOR, and JNK expression, suggesting an additional mechanism involving cell cycle regulation, cell motility, cell survival, and cell differentiation. Third, BME treatment also decreases steroidogenic activities in adrenocortical cancer cells by Western blotting and reporter gene assay. BME treatment of adrenocortical cancer cells results in a significant dose-dependent decrease in levels of NR5A1/SF1, MC2R, StAR proteins. Interestingly, we find that BME treatment decreases the level of phospho-CDK7, which is required, at least in part, for NR5A1/SF1 activation. Taken together, these data illustrate that inhibitory effect of bitter melon on the growth and proliferation of adrenocortical cancer cells through modulation of the cell cycle regulation and steroidogenic pathways. Therefore, BME can be used as a dietary supplement for prevention of adrenocortical 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 5587. doi:10.1158/1538-7445.AM2011-5587
Abstract 5620: Polymorphisms in steroid hormone genes and endometrial cancer risk
Authors: Doherty Jennifer A. , Weiss Noel S. , Fish Sherianne , Fan Wenhong , Loomis Melissa M. , Rossing Mary Anne , Zhao Lue Ping , Chen Chu 
Published: June 2012

Abstract
The incidence of endometrial cancer is increased in the presence of elevated circulating levels of estrogens, especially when inadequately opposed by progestins. Estrogens are catabolized via catechol estrogen formation, oxidation, glucuronidation, and sulfation. Thus, it is possible that interindividual variation in these pathways might influence a woman's risk of endometrial cancer. To test this hypothesis, we examined whether the presence of the minor alleles in 26 SNPs in the genes CYP17, CYP1A1, CYP1B1, CYP3A4, CYP3A5, COMT, SULT1A1, UGT1A1, UGT1A8, UGT2B4, UGT2B7, and UGT2B15 was associated with risk of endometrial cancer in a population-based case-control study in Washington State, with 727 cases ages 50-74 years diagnosed between 1994-2005, and 736 controls frequency-matched to the cases by age, county and reference year. Analyses were restricted to non-Hispanic white women and adjusted for frequency matching variables. Only SNPs in CYP1A1 (involved in the formation of 2-hydroxyestrogens) and SULT1A1 (involved in estrogen sulfation) were associated with endometrial cancer risk. The CYP1A1 rs4646903 C allele was associated with a decreased risk of endometrial cancer (per C allele odds ratio (OR) 0.75, 95% confidence interval (CI) 0.58-0.95; ORs and 95% CIs for CT and CC vs TT were, respectively: 0.81, 0.61-1.07, and 0.38, 0.15-0.93). The SULT1A1 rs9282861 A allele was associated with increased risk of endometrial cancer (per A allele OR 1.22, 95% CI 1.04-1.42; ORs and 95% CIs for AG and AA vs GG were, respectively: 1.20, 0.96-1.50, and 1.50, 1.06-2.12). Both of these polymorphisms have been reported to be associated with alterations in the ability to metabolize estrogens; the CYP1A1 rs4646903 C allele may be associated with increased inducibility and increased endometrial expression of CYP1A1, and therefore could be associated with potentially higher levels of the 2-hydroxyestrogens in the target tissue. The SULT1A1 rs9282861 A allele is associated with reduced sulfotransferase activity, which could possibly allow the accumulation of estrogens. Thus, the observed associations with each SNP are consistent with their putative biologic function. However, several studies have examined variation in these and other genes in the steroid hormone metabolism pathways and endometrial cancer risk, and there are reports of both positive and negative findings for many of the SNPs studied. If a small effect size is expected, then additional studies and pooled analyses are needed to clarify possible associations with each of these polymorphisms.
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 5620. doi:10.1158/1538-7445.AM2011-5620
Abstract 579: Cell death induction end-points to identify new cancer indications with high likelihood of response to dual PI3K /mTOR inhibitors
Authors: Huang Alan , Lehar Joseph , Pradhan Elina , Tomaso Emmanuelle Di , Villarroel Maria , Hackl Wolfgang , Quadt Cornelia , Fritsch Christine , Weiss Andreas , Brachmann Saskia , Schlegel Robert , Hofmann Francesco , Maira Michel 
Published: June 2012

Abstract
Constitutive activation of the PI3K pathway is driven by a variety of genetic and epigenetic abnormalities, such as PTEN deletions, mutations, genesilencing, PIK3CA mutations and/or enhanced engagement through genetic abnormalities in upstream RTKs. Targeted therapies against specific components of the PI3K pathway are therefore expected to produce positive outcome as single agents or in combination in cancers presenting these abnormalities. Two molecular entities are in full clinical development: NVP-BEZ235, a dual PI3K/mTOR inhibitor and NVP-BKM120, a pan-class I PI3K inhibitor without mTOR activity. In order to best position these agents clinically, we investigated their efficacy in models bearing PIK3CA, PTEN, HER2, or KRAS genetic alterations.
We previously demonstrated that NVP-BEZ235 in in vitro antiproferative activity was not predictive of preclinical antitumor response, in vivo. However, breast cancer models presenting either HER2 amplification or PIK3CA mutations or both were shown to be very sensitive to the compound and the use of cell death induction as an end-point was found to be predictive of strong antitumor activity in vivo. To further validate this finding, dual PI3K/mTOR targeting was phenocopied using an mTOR shRNA inducible system or an mTOR specific inhibitor (AZD8055) in combination with a pan-PI3K inhibitor, in various tumor models. Strong cell death signals were observed in 2 HER2 amplified / PIK3CA mutant breast cancer models but not in KRAS mutant cells or as PTEN silenced breast cancer cell lines, when subjected of PI3K/mTOR targeting. Moreover, in vivo, combination of a pure pan-PI3K with a pure mTOR inhibitor resulted in strong regression of HER2 amplified /PIK3CA mutant MDA-MB361 tumors.On the basis of these observations, NVP-BEZ235 was retested in a set of more then 150 tumor lines across various lineages, and cell death induction was determined. As expected, HER2 amplified /PIK3CA mutant breast cancer lines scored as sensitive. Other models from different indications and genetic background were also found to be sensitive to NVP-BEZ235. Validation studies of these new models and potential indications will be presented, and implications for further clinical trials of dual PI3K/mTOR or pure PI3K inhibitors discussed.
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 579. doi:10.1158/1538-7445.AM2011-579