bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 284: 17β-estradiol-induced expression of αEF1 confers tamoxifen resistance in breast cancer
Authors: Guo Shaocong , Hu Fen , Gao Yang , Zhu Tianhui , Yang Shuang 
Published: August 2012

Abstract
Background: Resistance to tamoxifen therapy is one of the major barriers to the successful treatment of breast cancer, and ER-α expression is currently the main biomarker of response to tamoxifen treatment. Elucidating the regulation of ER-α expression may provide new therapeutic targets for overcoming tamoxifen resistance. Materials and Methods: Quantitative RT-PCR, immunoblotting, and immunofluorescence were used to determine 17β-estradiol-induced expression of αEF1 and ER-α at the mRNA and protein levels in the presence or absence of ICI 182,780, PI-103, PKI, or BAY 11-7082. Luciferase assay was used to determine αEF1-driven transcriptional activities of the wild-type and mutant human ER-α promoters. Quantitative CHIP assay was used to detect the direct association of αEF1 with the wild-type human ER-α proximal promoter. Immunohistochemistry was used to determine the expression of αEF1 and ER-α protein in breast cancer specimens. Results: We found that 17β-estradiol up-regulated αEF1 expression in a dose- and time-dependent manner in MCF-7 breast cancer cells. Down-regulation of the ER-α significantly abolished this effect, showing that 17β-estradiol-induced expression of αEF1 is ER-dependent. Blockade of the PI3K or NF-κB pathway resulted in an interference on the up-regulation of αEF1 by 17β-estradiol. Interestingly, ectopic expression of αEF1 exhibited a repression on ER-α expression in MCF-7 cells. Luciferase and CHIP assays further confirmed that αEF1 transcriptionally inhibited the promoter activity of human ER-α by binding to its E2-box (CACCTG). Importantly, up-regulation of αEF1 expression rendered MCF-7 cells less sensitive to tamoxifen treatment, whereas adding ER-α comprised the effect of αEF1 on the cell sensitivity to tamoxifen. Through the study of breast cancer specimens, we found a strong inverse correlation between αEF1 and ER-α protein expression, further supporting the contribution of estrogen/αEF1/ER cascade to tamoxifen resistance in breast cancer. Conclusions: Our data indicates a key role of αEF1 in developing tamoxifen resistance in breast cancer, by altering ER-α expression. Given that re-expressing ER-α in ER-α-negative breast cancer can restore tamoxifen sensitivity, restoring ER-α expression by inhibiting αEF1 provides a potential new strategy for overcoming endocrine resistance.
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 284. doi:1538-7445.AM2012-284
Abstract 2862: Deregulated GSK3β sustains gastrointestinal cancer cells by modulating hTERT and telomerase
Authors: Minamoto Toshinari , Mai Wei , Kyo Satoru , Shakoori Abbas , Miyashita Katsuyoshi , Yokoi Kenji , Shimasaki Takeo , Motoo Yoshiharu , Kawakami Kazuyuki 
Published: August 2012

Abstract
Purpose: Glycogen synthase kinase-3β (GSK3β) regulates multiple cell signaling pathways and has been implicated in glucose intolerance, neurodegenerative disorders, and inflammation. We investigated the expression, activity, and putative pathologic role of GSK3β in gastrointestinal, pancreatic, and liver cancers. Experimental Design: Colon, stomach, pancreatic, and liver cancer cell lines; nonneoplastic HEK293 cells; and matched pairs of normal and tumor tissues of stomach and colon cancer patients were examined for GSK3β expression and its phosphorylation at serine 9 (inactive form) and tyrosine 216 (active form) by Western immunoblotting and for GSK3β activity by in vitro kinase assay. The effects of small-molecule GSK3β inhibitors and of RNA interference on cell survival, proliferation, and apoptosis were examined in vitro and on human colon cancer cell xenografts in athymic mice. The effects of GSK3β inhibition on human telomerase reverse transcriptase (hTERT) expression and telomerase activity were compared between colon cancer and HEK293 cells. Results: Cancer cell lines and most cancer tissues showed increased GSK3β expression and increased tyrosine 216 phosphorylation and activity but decreased serine 9 phosphorylation compared with HEK293 cells and nonneoplastic tissues. Inhibition of GSK3β resulted in attenuated cell survival and proliferation and increased apoptosis in most cancer cell lines and in HT-29 xenografts in rodents but not in HEK293 cells. GSK3β inhibition in colon cancer cells was associated with decreased hTERT expression and telomerase activity. Conclusion: The results indicate that deregulated GSK3β sustains gastrointestinal cancer cells survival through modulation of hTERT and telomerase.
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 2862. doi:1538-7445.AM2012-2862
Abstract 2868: Pancreatic tumor stromal cells express high levels of α-glutamyl transferase that may be employed to deliver a metabolism inhibitor to the tumor mass
Authors: Ramsay Emma E. , Decollogne Stéphanie , Joshi Swapna , Corti Alessandro , Pompella Alfonso , Apte Minoti , Hogg Philip J. , Dilda Pierre J. 
Published: August 2012

Abstract
Tumors of the pancreas have the most prominent stromal/desmoplastic reaction of all epithelial tumors. This reaction is mediated by the cancer-associated stellate cells. These cells interact closely with pancreatic cancer cells to promote cancer cell survival, local tumor growth and distant metastasis (1). We have found that cancer-associated human pancreatic stellate cells express up to 30-fold higher levels of α-glutamyl transferase (≥GT) on their surface than normal pancreatic stellate cells. βGT catalyzes the transfer of the α-glutamyl moiety of glutathione to an acceptor that may be an amino acid, a peptide or water (forming glutamate). This observation suggests that this enzyme could be used to deliver a αGT-activated prodrug to the tumor mass. We have tested this theory using the glutathionylated arsenical, GSAO. GSAO is converted to GCAO by cell surface αGT, which then crosses the plasma membrane and inactivates the mitochondrial inner-membrane transporter, adenine nucleotide translocase (2). The mitochondrial perturbation leads to proliferation arrest and then cell death. GSAO was converted to GCAO by cancer-associated stellate cells and this metabolism was blocked by the αGT inhibitor, ABBA. The activated GSAO inhibited proliferation of both tumor and endothelial cells by 43 to 100% and 41 to 75%, respectively. We also observed a positive correlation (R2=0.883) between the αGT activity of pancreatic tumor cells and proliferation arrest of co-cultured endothelial cells by GSAO. We have established an orthotopic model of human pancreatic cancer in mice where tumor cells are implanted without or with cancer-associated stellate cells. The anti-tumor efficacy of systemically administered GSAO is currently being evaluated in this model. These observations suggest that the high expression of αGT on pancreatic tumor stromal cells may be employed to deliver a αGT-activated prodrug to the tumor mass. 1. Vonlaufen, A., Phillips, P. A., Xu, Z., Goldstein, D., Pirola, R. C., Wilson, J. S., and Apte, M. V. (2008) Cancer Res. 68, 7707-7710 2. Dilda, P. J., Ramsay, E. E., Corti, A., Pompella, A., and Hogg, P. J. (2008) J. Biol. Chem. 283, 35428-35434
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 2868. doi:1538-7445.AM2012-2868
Abstract 2878: Anticancer effects of c-Met inhibitors in esophageal squamous cell carcinoma
Authors: Tzao Ching , Wang Chun-Ya , Lee Meng-Ching , Chen Ban-Hen , Sun Guang-Huan 
Published: August 2012

Abstract
Background: c-Met is a receptor tyrosine kinase (RTK) that has been shown to be a potential target of therapy in a variety of human cancers. We investigated if c-Met served as a potential therapeutic target in esophageal squamous cell cancer (ESCC). Methods: Cytotoxicity (MTT) assay, cell migration assay and cell cycle analysis by flow cytometry were conducted in KYSE 510 and 170 ESCC cell lines (kindly provided by Dr. Yutaka Shimada) in response to various concentrations of c-met inhibitors, SU11274 and PHA665752. Apoptosis of ESCC cell lines was detected by TUNEL assay. Cell cycle regulatory proteins, cyclin A and B1, tumor suppressors including Rb, p53 p21 and p27, and intrinsic apoptotic factors were determined by Western blot analysis. Mice inoculated with KYSE 170 ESCC cell line were used to test therapeutic response of c-met inhibitors in vivo. Results: SU11274 and PHA665752 significantly suppressed viability and migration of KYSE 170 and 510 ESCC cells with decreased expression of phosphorylated c-Met (p-c-Met). Expression of p21, p27, p53 and Rb was upregulated in ESCC cell lines treated with c-Met inhibitors while inducing G1/G2 cell cycle arrest and apoptosis. Tumor growth in vivo was significantly suppressed in response to treatment with c-Met inhibitors with decreased expression of p-c-Met within the mice tumors. Conclusion: c-Met inhibitors exerted significant anticancer effects in vitro and in vivo for ESCC cell lines, suggesting that c-Met may serve as a potential therapeutic target for ESCC.
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 2878. doi:1538-7445.AM2012-2878
Abstract 2882: Therapeutic effects of ormeloxifene on cervical cancer
Authors: Chauhan Neeraj , Maher Diane M. , Yallapu Murali M. , Ebeling Mara C. , Jaggi Meena , Chauhan Subhash C. 
Published: August 2012

Abstract
Background: Cervical cancer is one of the most common and deadly cancers among women worldwide and is strongly associated with persistent Human Papillomavirus (HPV) infection. HPV E6/E7 oncoproteins are well known to interfere with p53 and retinoblastoma (Rb) proteins and drive the development of cervical cancer. While screening for cervical cancer can reduce the incidence and mortality, treatment of advanced stage cervical cancer is difficult and often unsuccessful. Therefore, there is an urgent need for the development of additional treatment modalities. Ormeloxifene is a non-hormonal anti-estrogen oral contraceptive for human use and it effectively suppresses the highly proliferative decidual cells in the endometrium to inhibit egg implantation. Considering its strong anti-proliferative effect, we hypothesized that ormeloxifene may inhibit the growth of cervical cancer cells and may suppress the expression of HPV oncoproteins E6/E7. Methods: The effect of ormeloxifene on the proliferation of various cervical cancer cell lines (Caski, SiHa, C33A, and HT3) was determined by MTS and colony formation assay. Annexin V/7AAD and propidium iodide (PI) staining was analyzed by flow cytometry to determine ormeloxifene's effect on apoptosis and cell cycle inhibition, respectively. The expression of apoptotic proteins such as poly (ADP-ribose) polymerase (PARP), Caspase 3 and Caspase 9 was determined by immunoblotting. The potential of ormeloxifene to repress the expression of HPV E6/E7 oncogenes was determined by quantitative RT-PCR and immunoblotting analyses. Further, the efficacy of ormeloxifene to restore tumor suppressor proteins, such as p53 and Rb, was also determined by immunoblotting. Results: In all 4 cell lines, ormeloxifene effectively inhibited cervical cancer cell growth. Ormeloxifene treatment induced apoptosis in cervical cancer cells as determined by staining for Annexin V/7AAD and immunoblotting for cleaved PARP, Caspase 3, and Caspase 9. PI staining also clearly revealed that ormeloxifene treatment arrests Caski cells in the G0-G1 phase. Additionally, ormeloxifene treatment caused a marked decrease in the levels of HPV E6 and E7 oncogenes and restored the levels of p53 and Rb proteins in Caski cells. Conclusion: Our findings show that ormeloxifene significantly inhibits cervical cancer cell growth and down-regulates HPV E6/E7 oncogenes, therefore; ormeloxifene may be novel chemo-preventive and treatment method for the management of cervical 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 2882. doi:1538-7445.AM2012-2882
Abstract 2892: Enhancing anti cancer activity of PI103, a dual PI3K/mTOR inhibitor, by designing a self assembled Nanoformulation
Authors: Roy Bhaskar , Sengupta Poulomi , Soni Shivani , Papa Anne Laure , Kopparam Jawahar , Sarangi Sasmit , Pandey Ambarish , Basu Sudipta , Sengupta Shiladitya 
Published: August 2012

Abstract
The phosphoinositide 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway plays a pivotal role in the growth and survival of various cancers. Small molecule inhibitors targeting PI3K/AKT/mTOR pathway (eg. Wortmannin, LY294002, PI-103, PI828) are promising anti cancer agents. Major drawbacks of these drugs are their poor water solubility and off-target toxicity. Nanoscale drug delivery systems have been harnessed as drug carriers to target tumours through enhanced permeation and retention effect. In this study, we developed a nanoformulation of PI103, a potent dual PI3K/mTOR inhibitor, to improve delivery and reduce side effects. PI103 was encapsulated in a homogeneous self-assembled mixture of phosphatidylcholine and cholesterol. DSPE-PEG protective shell was introduced to increase its circulation time. Thin-film-hydration technique followed by extrusion through 200 nm porous membranes developed nanoparticles of 110-150 nm size with 0.15-0.20 mM drug loading. Release kinetics study confirmed the stability of this formulation in PBS for several days as well as a sustained release property in in-vitro Cell Lysate system. In-vitro cell proliferation assay demonstrated improved cytotoxicity of nanoformulated PI103 in murine breast cancer cell line 4T1 and K-ras upregulated and PTEN suppressed ovarian cancer model cells. Fluorescent Activated Cell Sorting (FACS) analysis with FITC tagged Annexin-V, an early apoptosis marker, showed increased apoptosis with the nanoformulation than the free drug. Western blot analysis expressed more potent inhibition of PI3 kinase/Akt pathway by the nanoformulated PI103. These results indicate that nanoformulation can enhance the potential of PI103.
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 2892. doi:1538-7445.AM2012-2892
Abstract 3011: Correlation of PERK activation with increased GRP78-binding in UVB-irradiated HaCaT cells
Authors: Tong Lingying , Wu Shiyong 
Published: August 2012

Abstract
Ultraviolet (UV) light has been shown to be a potential human carcinogen, and it is widely accepted that UV exposure can impact protein expression via both transcriptional and translational regulation. PERK is one of the eIF2α kinases that is activated and inhibits protein synthesis upon UV irradiation. However, the mechanism for UV-induced PERK activation is not fully elucidated. In this study, we evaluated the role of GRP78/BiP, an inhibitory PERK-binding protein, in the regulation of PERK activity in UVB irradiated cells. Our data showed that while PERK expression was reduced in both human keratinocytes (HaCaT) and mouse embryonic fibroblasts (MEF) cells, GRP78/BiP expression remained steady in HaCaT and slightly increased in MEF cells after UVB irradiation. Our data also showed that the Tyr phosphorylation of PERK, an indication of activation, was increased after UVB irradiation, which confirmed the role of PERK in UV-induced translational regulation. Unexpectedly, a co-immunoprecipitation analysis indicated PERK activation was accompanied with an increase in PERK-bound GRP78/BiP in the irradiated HaCaT cells. Based on these results, we propose that UV-induced PERK activation might be GRP78/BiP-independent, and its activation pathway in HaCaT cells may be unique from other cell lines.
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 3011. doi:1538-7445.AM2012-3011
Abstract 3012: The mechanism of UV-induced and prohibitin-mediated apoptosis
Authors: Wu Qiong , Wu Shiyong 
Published: August 2012

Abstract
Ultraviolet B (UVB) light is a potential environmental carcinogen, which has been shown to cause various skin cancers. Normally, UV-damaged cells are eliminated by the self-protective apoptosis response. UVB-induced apoptosis can be regulated by modification of major lipid raft components, such as cholesterol and ceramide. Upon UVB irradiation, an alteration of lipid raft composition leads to the recruitment/activation of raft-associated proteins and initiates downstream apoptotic signaling pathways. To identify potential regulators of UVB-induced apoptosis, we used 2D gel electrophoresis to identify the raft proteins that are altered after UVB-irradiation. Our data shows that levels of several raft proteins, including prohibitin (PHB), were changed after UVB-irradiation. PHB plays a critical role in many cell functions, such as cell-cycle control, cell proliferation, senescence, development, apoptosis, and tumor suppression. However, no reports implicate PHB-mediated apoptosis upon UVB irradiation. We now demonstrate that while the total PHB expression does not change, PHB is enriched in lipid rafts after UVB irradiation. Immunoprecipitation analysis shows that UVB alters the binding ability of PHB, Raf, and Akt, and decrease PHB phosphorylation. PHB siRNA knockdown cells exhibited an increased phosphorylation of Akt and ERK, and increased cell apoptosis after UVB irradiation. Based on these results, we propose that PHB regulates UVB-induced apoptosis through lipid raft translocation and alteration of Akt and Raf/ERK signaling pathways.
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 3012. doi:1538-7445.AM2012-3012
Abstract 3025: CXCR4 is expressed in the nucleus of metastatic prostate cancer cells
Authors: Hewage Ayesha S. Don Salu , Hinton Cimona V. 
Published: August 2012

Abstract
Most prostate cancer-related deaths are due to the advancement of the tumor to a metastatic disease. The C-X-C Chemokine Receptor 4 (CXCR4) is a G-protein coupled receptor (GPCR) involved in the metastasis of various cancers, including the prostate. CXCR4 is generally regarded as a plasma membrane receptor; the canon concept of GPCR signaling holds that receptors located at the plasma membrane respond to secreted agonist stimulation. GPCRs, however, have also been observed at other intracellular organelles, including the nuclear membrane. Several cancer models have positively observed expression of a nuclear form of CXCR4 in advanced stage tissues and tumors with a poor prognosis. The significance of these receptors having a dualistic localization pattern is that nuclear receptors can escape from chemotherapy, since most therapeutics are hydrophobic small molecules targeted towards membrane bound receptors, which cannot pass through non-polar regions of the plasma membrane. An initial search of the CXCR4 sequence through the PredictNLS software program revealed a putative, nontraditional nuclear localization sequence, RPRK. We probed prostate cancer tissues for CXCR4 and observed a higher nuclear expression in high grade prostate tumors, compared to low grade, and no detectable CXCR4 in normal human prostate tissue by immunohistochemistry. Subcellular fractionations of prostate cancer cell lines (PC3, DU145 and 22RV1) and normal prostate epithelial cells (RWPE1) demonstrated positive expression of CXCR4 in both nuclear and cytoplasmic fractions, which were confirmed by immunocytochemistry analysis, independent of exogenous SDF1α stimulation. Based on our results, we suggest that CXCR4 is alternately expressed in the nucleus of advanced prostate cancer, which may enhance prostate cancer metastasis. To determine the origin of nuclear CXCR4, the a kinetic localization study confirmed that CXCR4 translocates to the nucleus from the plasma membrane at 37°C, which was inhibited when the same reaction was performed at 4°C. In conclusion, expression and localization of a nuclear CXCR4 may contribute to the advancement of prostate cancer to a metastatic disease, and aid tumors in escaping from therapy. Our studies will contribute to the development of therapeutics towards CXCR4, as current options are targeted towards membrane receptors, which may be ineffective if CXCR4 located and functional inside of the cell.
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 3025. doi:1538-7445.AM2012-3025