bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5715: Modulation of Radiation Response after TGFβ signaling Blockade in Non-small Cell Lung Cancer (NSCLC) Cell Carcinomas
Authors: Du Shisuo , Bouquet Fanny , Pellicciotta Ilenia , Parry Renate , Barcellos-Hoff Mary Helen 
Published: August 2012

Abstract
Lung cancer remains one of the most prevalent and deadliest malignancies worldwide. Radiotherapy (RT) is a major therapeutic modality for inoperable non-small cell lung cancer (NSCLC). There is substantial evidence that ionizing radiation triggers activation of TGFβ especially in lung, breast and liver tumor. TGFβ inhibition prior to IR inhibits the DNA damage response in epithelial cells via blockade of ATM kinase activity (Cancer Res 62:5627, 2002; Cancer Res 66:10861, 2006) and sensitizes radiation responses in breast cancer cell lines and tumors (Clin Cancer Res 2011;17:6754-6765.). The current studies test whether TGFβ blockade prior to irradiation modulates radiation response of NSCLC cell lines, NCI-H1299, NCI-H292, H460 and Lewis Lung Cancer (LLC), assessed in vitro and in vivo. All NSCLC cell lines responded to TGFβ by phosphorylation of Smad2, which was blocked by LY364947, a small molecule TGFβ type 1 receptor inhibitor. NCI-H1299 and LLC were insensitive to TGFβ growth inhibition in vitro. LY364947 increased radiosensitivity in NCI-H1299 and H460 in clonogenic assays. Consistent with increased clonogenic cell death, TGFβ inhibition also compromised radiation-induced phosphorylation of H2AX and ATM in NCI-H1299. Treatment of cultured LLC cells with either small molecule TGFβ type 1 receptor inhibitor or TGFβ neutralizing antibody, 1D11, significantly increased LLC radiosensitivity as measured by clonogenic assay. Furthermore, C57BL mice bearing subcutaneous LLC tumors treated before and after RT with 1D11 or 13C4 isotype control antibody (20 mg/kg i.p.) resulted in greater tumor growth delay compared to RT and control antibody. Together, these data indicate that TGFβ inhibition prior to radiation attenuates DNA damage responses, enhances clonogenic cell killing, and promotes tumor growth delay. Given the recognized role of radiation-induced TGFβ in lung fibrosis, the therapeutic index for RT could be significantly increased if circumstances are defined in which TGFβ inhibition during RT both enhances lung cancer radiosensitivity and protects normal lung.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5715. doi:1538-7445.AM2012-5715
Abstract 5727: Competitive inhibition of mTOR results in tumor specific radiosensitization
Authors: Hayman Thomas J. , Bae Heekyong , Camphausen Kevin , Tofilon Philip J. 
Published: August 2012

Abstract
Translational control of gene expression has been implicated as a component of the cellular response to ionizing radiation (IR). The mammalian target of rapamycin (mTOR) is a critical kinase in the regulation of translation. mTOR exists in two distinct complexes: mTORC1 and mTORC2. mTORC1 regulates 4E-BP1 and p70-s6k, whereas mTORC2 regulates several AGC kinases including AKT. Most studies of mTOR have focused on the use of the allosteric inhibitor rapamycin and its analogs, which incompletely inhibit mTORC1 and do not inhibit mTORC2. In contrast, newly developed competitive mTOR inhibitors (e.g. PP242) inhibit mTORC1 output more completely and inhibit mTORC2. In the study described here, we compared the effects of rapamycin and PP242 on cellular radiosensitivity using a clonogenic assay. In two tumor cell lines originating from different histologies, U251 and MDA-MB-231, PP242 treatment 1h before irradiation increased radiosensitivity with DEFs (dose enhancement factors at 0.1 surviving fraction) of 1.52 and 1.34 respectively, whereas rapamycin had no effect. However, PP242 had no effect on the radiosensitivity of the normal human fibroblast cell line, MRC9. PP242 treatment of U251 cells resulted in a dose-dependent increase in radiosensitivity. Furthermore, addition of PP242 immediately, 1, or 6h after IR resulted in increased radiosensitivity with DEFs of 1.60, 1.50, and 1.26, respectively. To investigate the mechanism of this radiosensitization U251 cells were treated with PP242, irradiated (2Gy) and stained for γH2AX, a marker of DNA double strand breaks (DSBs). PP242 exposure significantly delayed the dispersal of radiation-induced γH2AX foci, consistent with an inhibition of DSB repair. Under conditions of clonogenic survival, exposure of U251 or MDA-MB-231 cells to 2Gy resulted in no detectable increase in mTOR output. PP242 treatment of both tumor lines resulted in complete inhibition of mTORC1/2 output whereas rapamycin only partially inhibited mTORC1 and did not inhibit mTORC2. m7-GTP batch chromatography showed PP242 induced a decrease in cap-bound eIF4G and an increase in cap-bound 4E-BP1, while rapamycin slightly increased 4E-BP1 binding and had no effect on eIF4G binding. Consistent with the effects on cap-complex formation, PP242 treatment caused a considerably greater decrease in polysome abundance than rapamycin. These results suggest that competitive inhibitors of mTOR, in contrast to rapalogs, induce tumor selective radiosensitization. Moreover, the mechanism appears to involve the inhibition of DSB repair and the suppression of translation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5727. doi:1538-7445.AM2012-5727
Abstract 573: Deguelin inhibits the expression of estrogen receptor alpha in human breast cancer cells
Authors: Alimirah Fatouma , Mehta Rajeshwari R. , Peng Xinjian , Mehta Rajendra G. 
Published: August 2012

Abstract
The estrogen receptor alpha (ERα), a nuclear receptor and transcription factor governs the action of estrogen. This hormone is the major contributor to normal breast development and breast carcinogenesis. Thus, antiestrogens are widely utilized to treat and circumvent the progression of hormone receptor positive breast cancer. However, resistance to these agents develops after sustained use and major risk factors such as enhanced susceptibility to endometrial cancer have been associated with this type of treatment. In an effort to develop natural therapeutic compounds against ERα positive breast cancer, the effect of deguelin, a rotenoid isolated from an African plant; Mundulea sericea on ERα positive human breast cancer cells was investigated. Here we report that deguelin treatment downregulated the expression of ERα protein in a dose dependent manner in MCF-7 and T47D human breast cancer cell lines as determined by immunoblotting. Quantitative RT-PCR analysis revealed that the mRNA expression of ERα target genes Cathepsin D (CTSD), Trefoil factor 1 (TFF1) and the Progesterone receptor (PGR) was also downregulated by 50% in the presence of deguelin in MCF-7 cells. Furthermore, deguelin treatment significantly inhibited the proliferation of these two cell lines. Importantly, estrogen mediated stimulation of cell growth was reduced by 30% in MCF-7 cells after deguelin treatment. Together these findings suggest that deguelin suppresses ERα signaling, paving the way for the development of a novel natural therapeutic agent against endocrine receptor positive breast cancer. Future studies are aimed at deciphering the molecular mechanisms by which deguelin adversely affects ERα function. (This work was supported by NCI CA140321).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 573. doi:1538-7445.AM2012-573
Abstract 5742: Up-regulation of mitochondrial chaperone TRAP1 in cancer precursors associated with chronic inflammation
Authors: Chen Ru , Pan Sheng , Bronner Mary , Lai Keith , Crispin David A. , Lai Lisa A. , Brentnall Teresa A. 
Published: August 2012

Abstract
Chronic ulcerative colitis (UC) is an inflammatory bowel disease that predisposes to colorectal cancer. In chronic UC patients, the colon epithelium undergoes repeated cycles of inflammation and tissue repair, resulting in oxidative stress and accumulation of reactive oxidative species (ROS). Excessive ROS can cause oxidative stress, which may subsequently lead to damage in DNA, proteins and lipids. Using proteomics analysis of colonic mucosa from UC patients with neoplasia, we identified TNF receptor-associated protein 1(TRAP1) in the UC cancer precursors. TRAP1 is a mitochondrial chaperone which protects against oxidative stress and apoptosis. We further investigated TRAP1 in the progression of UC-associated colorectal cancer using immunohistochemistry and tissue microarray. Quantification of protein oxidation in the colonic epithelia revealed that oxidative stress was present in the colonic mucosa in both UC patients with dysplasia/cancer (progressors) and UC patients without dysplasia/cancer (non-progressors). However, TRAP1 was only up-regulated in UC progressors, but not in the non-progressors. Moreover, up-regulation of TRAP1 preceded the histological changes: it was present in both the dysplastic and non-dysplastic tissue of the UC progressors. We then investigated the cellular proteome changes underlying oxidative stress, and found that up-regulation of TRAP1 could be induced by oxidative stress. These results suggest that UC cancer arises in the setting of oxidative stress. Such oxidative stress subsequently induces the cytoprotective protein TRAP1. TRAP1 in turn appears to promote cancer progression by preventing the oxidative-damaged epithelial cells from undergoing apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5742. doi:1538-7445.AM2012-5742
Abstract 5752: Expression and biological significance of adiponectin receptors in papillary thyroid carcinoma
Authors: Cheng Shih-Ping , Liu Chien-Liang , Hsu Yi-Chiung , Chang Yuan-Ching , Huang Shih-Yuan , Lee Jie-Jen , Chen Yu-Jen 
Published: August 2012

Abstract
Obesity is associated with a higher incidence of thyroid cancer. Adiponectin is one of the most abundant adipokines with pleiotropic roles in metabolism and in the development and progression of cancer. This study aimed to investigate the possible association between the expression of adiponectin receptors (AdipoR1 and AdipoR2) and clinicopathological variables in papillary thyroid cancer. We found that levels of AdipoR1 and AdipoR2 were commonly increased in thyroid cancer compared with adjacent normal thyroid tissues. Thyroid cancer cells expressed AdipoR1 and AdipoR2, which were attenuated by histone deacetylase inhibitor trichostatin A. We determined the expression of AdipoR1 and AdipoR2 by immunohistochemical staining in primary tumor samples and metastatic lymph nodes. AdipoR1 was expressed in 27% of primary tumors and AdipoR2 in 47%. AdipoR1 expression correlated with AdipoR2 expression in primary tumors and in metastatic lymph nodes. Tumor AdipoR1 expression was associated with larger tumor size, whereas negative AdipoR2 expression was significantly associated with extrathyroidal invasion and multicentricity. Patients in the high AMES risk group had negative tumor expression of AdipoR1 and AdipoR2. Collectively, altered expression of adiponectin receptors in thyroid cancer supports a potential role in the pathogenesis of thyroid cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5752. doi:1538-7445.AM2012-5752
Abstract 583: Physiological concentrations of genistein reduced ER-α promoter methylation and increased ER-α expression in prostate cancer cells
Authors: Mahmoud Abeer M. , Yang Wancai , Al-Alem Umaima , Bosland Maarten C. 
Published: August 2012

Abstract
Prostate cancer is the most common malignancy and the second leading cause of cancer death among men in the United States. The lower incidence and mortality rates of prostate cancer in Asian population were correlated to the high dietary consumption of isoflavone-rich soy. One of the most abundant and potent isoflavones in soy is genistein which has an estradiol like structure and high affinity to estrogen receptor-α (ER-α). It has been suggested that genistein exerts its anti-cancer effects through binding to ER-α, the later has anti-proliferative and pro-apoptotic effects in prostate cancer. ER-α is mainly expressed in prostate epithelial cells and is downregulated in localized prostate cancer with increasing grade from Prostatic Intraepithelial Neoplasia (PIN) through low to high Gleason grade. This expression pattern supports the notion of a tumor suppressor role of ER-α. Therefore, ER-α agonists may be potential chemopreventive and therapeutic agents for prostate cancer. One of the mechanisms by which ER-α is suppressed in prostate cancer is promoter methylation, the extent of which correlates with the ER-α expression level which in turn may be linked to the degree of aggressiveness of prostate cancer. We examined the effects of physiological range of genistein concentrations (0.5, 1, and 10µM) on ER-α promoter methylation and ER-α expression in LNCaP, LAPC-4, and PC-3 prostate cancer cells that exhibit various basal levels of ER-α expression. We demonstrated for the first time that genistein caused a significant dose-dependent reduction in ER-α promoter methylation in LNCaP and LAPC-4 cells, using methylation specific PCR. There was a corresponding dose-related increase in ER-α mRNA and protein levels in these two cell lines assayed by quantitative RT-PCR and immunoblotting, respectively. However, ER-α expression levels and ER-α promoter methylation were not changed in PC-3 cells, which could be attributed to the low basal level of ER-α promoter methylation and the high basal level of ER-α expression in this cell line. These findings suggest that physiological concentrations of genistein is capable of reactivating tumor suppressor pathways by reversing ER-α promoter methylation with a subsequent restoration of the level of ER-α expression in prostate cancer cells that have higher basal levels of methylation. (Supported in part by Grant No. CA116195)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 583. doi:1538-7445.AM2012-583
Abstract 591: Licochalcone E inhibits solid tumor growth and lung metastasis of 4T1 murine mammary carcinoma cells in the BALB/c mouse orthotopic model
Authors: Park So Young , Kwon SooJin , Jeon Jae Ho , Jun Jong Gab , Park Jung Han Yoon 
Published: August 2012

Abstract
Licochalcone E a phenolic constituent of licorice that is reported to exert excellent anti-cancer effects. In the present study, to investigate the effect of licochalcone E oral administration on the solid tumor growth and metastasis of breast cancer cells, 4T1 cells were injected into the inguinal mammary fat pads of syngeneic female BALB/c mice. One week after the injection the mice were subjected to oral gavage for 25 days with licochalcone E (0, 7, or 14 mg/kg body weight/day). Licochalcone E treatment induced a significant reduction in solid tumor growth, which was accompanied by 1) reduced Ki67 (prototypic cell cycle related nuclear antigen), cyclin-dependent kinase (CDK)2, CDK4, cyclin A, and cyclin D1 and 2) increased numbers of TUNEL-positive apoptotic cells with increased Bax and cleaved caspase-3 expression but reduced Bcl-2 expression in tumor tissues. Licochalcone E also reduced the expression of hypoxia inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), VEGF-R2, CD31 (platelet endothelial cell adhesion molecule-1), VEGF-C and LYVE-1 (lymphatic vessel endothelial receptor-) in tumor tissues. In addition to tumor growth, oral licochalcone E administration markedly reduced the number of pulmonary tumor nodules. In lung tissues, licochalcone E induced a significant reduction in the levels of cytokines and angiogenesis-related proteins including DPPIV (CD26), endoglin (CD105), MMP-9, C5a, interleukin (IL)-1ra, IL-16, MIG (CXCL9). In vitro culture studies showed that licochalcone E dose-dependently inhibited the migration of MDA-MB-231 human breast cancer cells at concentrations of 0-20 μmol/L without significant changes in cell viability. Licochalcone E significantly reduced secretion of matrix metalloproteinase-9, urokinase-type plasminogen activator and VEGF in concentration-dependent manners in MDA-MB-231 cells. These results demonstrated that licochalcone E inhibits solid tumor growth and metastasis of breast cancer cells and these effects were mediated via the reduction of a wide variety of cytokines and chemokines, which subsequently inhibits tumor angiogenesis, lymphangiogenesis, proliferation, and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 591. doi:1538-7445.AM2012-591
Abstract 599: Regulation of hypoxia-inducible factor stability by peptidyl prolyl isomerase Pin1
Authors: Han Hyeong-jun , Choi Bu Young , Choi Min-A , Hahn Young-il , Park Ji-Hyeon , Surh Young-Joon 
Published: August 2012

Abstract
Pin1 is an isomerase that binds to phosphorylated Ser/Thr-Pro motifs and regulates a subset of phosphoproteins through isomerization of the phosphorylated bonds. Pin1 has been reported to play an important role in differentiation, cell proliferation and immune responses. Interestingly, Pin1 is overexpressed in many types of cancer tissues including breast, prostate, lung and colon. However, molecular mechanism underlying its oncogenic functions has not been fully elucidated. Here, we report that Pin1 directly or indirectly interacts with hypoxia-inducible factor (HIF) -1α and -2α in HCT116 cells. Pin1 can bind both HIF-1α and -2α in vitro. We also found that Pin1 interacted more strongly with HIF-2α than with HIF-1α at the endogenous level. Pin1 binding may cause stabilization of HIF-1α and HIF-2α protein, given that their levels were significantly increased under hypoxic condition. Pin1 knockdown decreased the expression of HIF-1α and HIF-2α proteins and vascular endothelial growth factor (VEGF) mRNA under hypoxic conditions. On the other hand, overexpression of Pin1 resulted in an increase in HIF-1α protein levels in hypoxic cells, and enhanced hypoxia-induced VEGF transcriptional activation. These results suggest that Pin1 interplays with HIF-1α and -2α, and is a potential chemopreventive and therapeutic target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 599. doi:1538-7445.AM2012-599
Abstract 60: KLF5 deletion promotes but does not initiate prostate carcinogenesis
Authors: Xing Changsheng , Fu Xiaoying , Sun Xiaodong , Dong Jin-Tang 
Published: August 2012

Abstract
KLF5 (Kruppel-like factor 5) is a basic transcription factor that is abundant in proliferating epithelial cells. Its locus at 13q21 is frequently deleted in human prostate cancer, suggesting a tumor suppressor function. Our previous study showed that TGF-beta, which is a differentiation signal for normal proliferating progenitor cells, acetylates KLF5 to reverse its function. Unacetylated KLF5 (unAc-KLF5) is pro-proliferative but acetylated KLF5 (Ac-KLF5) works with TGF-β to inhibit cell proliferation. Here we generated a Klf5-floxed mouse strain in which exons 2 and 3 of Klf5 are flanked by loxP sequences. By crossing Klf5-floxed mice with PB-Cre4 transgenic mice, we were able to delete the Klf5 gene specifically in prostatic epithelial cells. Because knockout of both Pten alleles induces prostate carcinoma, we also crossed Klf5-floxed mice with Pten-floxed mice to investigate Klf5 function in tumor progression. At different time points, prostates were collected and histological and molecular analyses were performed. We found that knockout of one Klf5 allele mainly increased cell proliferation and caused epithelial hyperplasia but was insufficient to initiate prostatic intraepithelial neoplasia (PIN). On the other hand, knockout of both Klf5 alleles mainly induced apoptosis in prostate epithelia. When combined with Pten knockout, the apoptosis was prevented due to the activation of PI3K survival signaling, making Klf5 null cells survive. With the deletion of one Pten allele, Klf5 deletion significantly increased cell proliferation and promoted the development of hyperplasia and PIN. When both Pten alleles were deleted, Klf5 deletion significantly enhanced tumor development, as indicated by increased tumor size and elimination of luminal structures. Immunohistochemical staining proved that cell cycle regulator p15 was downregulated in Klf5 knockout mice. Deletion of Klf5 also significantly induced phosphorylation of Erk1/2 MAPK and further increased Akt activity. In normal prostates, total Klf5 was detected in both luminal and basal cells of the prostate, while unAc-Klf5 and Ac-Klf5 were detected in basal and luminal cells respectively. In addition, oncogenic signals, such as Pten knockout, reduced Ac-Klf5 in differentiated luminal cells. In conclusion, deletion of Klf5 promotes cell proliferation and makes cells susceptible to other factor-induced carcinogenesis in the prostate, probably because of impaired proliferation-inhibitory function of Ac-Klf5.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 60. doi:1538-7445.AM2012-60