bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1010: Chronic nicotine inhibits apoptosis induced by chemotherapeutic drugs in pancreatic ductal adenocarcinoma (PDAC)
Authors: Banerjee Jheelam , Al-Wadei Hussein A. N. , Schuller Hildegard M. 
Published: June 2012

Abstract
Smoking is an established risk factor for pancreatic cancer. More than 95% of all pancreatic cancers are pancreatic ductal adenocarcinomas (PDACs). Our data has earlier established that nicotine contributes to the progression of smoking associated PDAC by increasing the systemic levels of the stress neurotransmitters adrenaline and noradrenaline in pancreatic cancer xenografts. These findings suggested that development and progression of PDAC is subject to significant modulation by stimulatory stress neurotransmitters. Here we demonstrate that nicotine abrogates the apoptotic activity of gemcitabine, gefitinib, and meloxicam, which are standard therapy for PDAC, in a variety of human PDAC cell lines. We first evaluated the effect of gemcitabine, gefitinib and meloxicam on cell proliferation using a varied range of concentrations and timepoints on pancreatic cancer cell lines PANC-1 and BXPC-3. The results demonstrated that all the three anti-cancer drugs significantly inhibited the proliferation of pancreatic cancer cells PANC-1 and BXPC-3. The IC50 values were determined for optimal concentration and timepoint. It was next examined whether chronic nicotine could confer protection against apoptosis induced by gemcitabine, gefitinib, and meloxicam, which are widely used to treat PDAC. Cells were stimulated with 1 µM nicotine (pre-determined concentration) in the presence or absence of the IC50 concentrations of the indicated drugs. Our results indicated that nicotine suppresses apoptosis induced by gemcitabine, gefitinib, and meloxicam in pancreatic cancer cells, as measured by TUNEL assays, viability assays and western blotting of apoptosis associated proteins. In conclusion, the antiapoptotic effects of nicotine, negatively impacts the chemosensitivity of PDAC cells against anticancer drugs. These findings suggest that continued exposure to nicotine during cancer therapy may significantly reduce the responsiveness to anti-cancer agents.
This work is supported by grants RO1CA130888 and RO1CA042829 with 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 1010. doi:10.1158/1538-7445.AM2011-1010
Abstract 1012: Osteopontin mediates loss of tumor suppressive activity of Merlin in breast cancer
Authors: Morrow K. Adam , Metge Brandon J. , Das Shamik , Ye Keqiang , Mulekar Madhuri S. , Tucker J. Allan , Samant Rajeev S. , Shevde Lalita A. 
Published: June 2012

Abstract
The neurofibromatosis type 2 (NF2) tumor suppressor gene encodes a cytoskeletal/membranous protein, Merlin. Inactivation of the NF2 gene is known to cause tumors of the nervous system in humans and multiple cancers in mice. Although Merlin's role as a tumor suppressor has been well studied in other systems, its function in breast cancer is unknown.
In this study, we have determined that the expression of Merlin protein is decreased in breast cancer tissues. Concomitantly, we observed increased expression of osteopontin (OPN), a malignancy-promoting protein that induces activation of Akt phosphorylation. Thus, there is an inverse correlation between the expression of Merlin and OPN in breast cancer. Ectopic restoration of Merlin in breast cancer cells significantly reduced attributes of malignant behavior as assessed in vitro by foci formation, soft agar colony formation, and invasion. In vivo, breast cancer cells stably expressing Merlin displayed reduced tumor growth and progression in athymic mice. Further, our investigations reveal that OPN-initiated activation of Akt signaling results in phosphorylation of Merlin at Serine 315 that targets it for proteasome-mediated degradation.
Thus, our studies elucidate the utility of Merlin as an important biomarker in breast cancer and also identify a novel mechanism for the loss of Merlin expression in breast cancer. Moreover, our studies demonstrate the ability of Merlin to act as a tumor suppressor in breast 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 1012. doi:10.1158/1538-7445.AM2011-1012
Abstract 1014: Induction of human steroid sulfatase by TNF-α through PI3-K/Akt signaling pathway in PC-3 human prostate cancer cells
Authors: Chun Young-Jin , Suh Bo-Young , Park Na-Hee , Jung Jin-Joo , Kim Donghak 
Published: June 2012

Abstract
Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and has a pivotal role in regulating the formation of biologically active estrogens. STS may help support the growth of hormone-dependent cancers, including prostate cancers and is considered as a new promising drug target for treating estrogen-mediated cancer. However, the molecular mechanism of STS expression is still not well-known. Previously, cytokines such as TNF-α and IL-6 were known to increase the activity of STS but the changes in expression have not been completely elucidated. To investigate whether cytokines are able to regulate transcription of STS gene, we studied the effect of TNF-α on STS expression in human prostate cancer PC-3 cells. Western blot and RT-PCR analyses showed that treatment with TNF-α significantly induced expression of mRNA level and protein level of STS in concentration- and time-dependent manners. Treatment with TNF-α resulted in a strong increase in the phosphorylation of Akt on Ser 473 and when the cells were treated with PI3-K inhibitors such as LY294002 or wortmannin or Akt inhibitor (Akt inhibitor IV) together, STS expression induced by TNF-α was significantly blocked. Moreover, inhibition of Akt activation by transfecting dominant-negative Akt plasmid also prevented TNF-α -mediated STS gene expression. Taken together, these data strongly suggest that TNF-α induces STS expression through PI3-K/Akt signaling pathway in PC-3 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 1014. doi:10.1158/1538-7445.AM2011-1014
Abstract 1017: Phosphorylation of histone H2AX at Ser139 and a new phosphorylation site Ser16 by RSK2 decreases H2AX ubiquitination and inhibits cell transformation
Authors: Zhu Feng , Zykova Tatyana , Peng Cong , Zhang Jishuai , Cho Yong-Yeon , Zheng Duo , Yao Ke , Ma Wei-Ya , Lau Andy T.Y. , Bode Ann M. , Dong Zigang 
Published: June 2012

Abstract
Histone H2AX is a histone H2A variant that is ubiquitously expressed throughout the genome. It plays a key role in the cellular response to DNA damage and has been designated as the histone guardian of the genome. H2AX deficiency decreases genomic stability and increases tumor susceptibility of normal cells and tissues. However, the role of H2AX phosphorylation in malignant transformation and cancer development is not totally clear. We found that ribosomal S6 kinase 2 (RSK2) directly phosphorylates H2AX at Ser139 and also at a newly discovered site, Ser16. EGF-induced phosphorylation of H2AX at both sites was decreased in RSK2 knockout cells. Phosphorylated RSK2 and H2AX co-localized in the nucleus following EGF treatment and the phosphorylation of H2AX by RSK2 enhanced the stability of H2AX and prevented cell transformation induced by EGF. RSK2 and DNA-PK, but not ATM or ATR, are required for EGF-induced phosphorylation of H2AX at Ser139. However, only RSK2 is required for phosphorylation of H2AX at Ser16. Phosphorylation of histone H3 was suppressed in cells expressing wildtype H2AX compared with H2AX knockout (H2AX-/-) cells. EGF-associated AP-1 transactivation activity was dramatically lower in H2AX-/- cells overexpressing wildtype H2AX compared with H2AX-/- cells expressing mutant H2AX-AA. Thus, the RSK2/H2AX signaling pathway negatively regulates the RSK2/histone H3 pathway and therefore maintains normal cell proliferation.
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 1017. doi:10.1158/1538-7445.AM2011-1017
Abstract 1026: Correlation of complex signaling pathway interactions with cell migration in a combined phosphorylation-cell migration assay
Authors: Chen Huaxian , Draney Daniel , Olive Michael 
Published: June 2012

Abstract
The acquisition of the ability of a cell to migrate, a process critical to tumor progression, is dependent on the activation of key cell signaling pathways. Screening assays that simultaneously quantify cell migration and the activity of the underlying signaling kinases may facilitate more efficient drug development. We report here an assay that allows simultaneous assessment of cell migration and pathway activity. The assay was performed in a commercially available microtiter plate and used near-infrared detection to achieve high sensitivity and reproducible results. The quality of the assay as determined by Z-factor analysis was 0.7 for migration and 0.58 for detection of phosphorylation. To model the drug screening process, we examined the effects of inhibitors of IGF-1R, PDGFR, and EGFR on cell migration and phosphorylation of AKT and ERK. An IGF-1R inhibitor strongly decreased both cell migration and phosphorylation of AKT and ERK. A PDGFR inhibitor showed a similar effect, but to a lesser degree. Inhibitors of PI-3 kinase/AKT and MEK also decreased cell migration but had surprising effects on the phosphorylation of AKT and ERK. Inhibition of MEK reduced phosphorylation of ERK to undetectable levels, yet did not completely abolish cell migration. Instead, AKT phosphorylation increased significantly. Likewise, inhibition of AKT decreased but did not abolish migration and increased ERK phosphorylation. The combination assay effectively assessed both migration and pathway activity as well as pathway crosstalk, a feature that should be useful for drug development.
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 1026. doi:10.1158/1538-7445.AM2011-1026
Abstract 1028: Hypoxia induces Notch signaling and promotes breast cancer metastasis by stimulating growth and self renewal of cancer stem-like cells
Authors: Xing Fei , Okuda Hiroshi , Watabe Misako , Kobayashi Aya , Pai Sudha K. , Liu Wen , Pandey Puspa R. , Fukuda Koji , Hirota Shigeru , Sugai Tamotsu , Wakabayashi Go , Koeda Keisuke , Kashiwaba Masahiro , Suzuki Kazuyuki , Chiba Toshimi , Endo Masaki , Watabe Kounosuke 
Published: June 2012

Abstract
Notch signaling is often and aberrantly activated by hypoxia during tumor progression; however, the exact pathological role of hypoxia-induced Notch signaling in tumor metastasis is as yet poorly understood. In this study, we aimed to define the mechanism of Notch ligand activation by hypoxia in both primary tumor and bone stromal cells in the metastatic niche and to clarify their roles in tumor progression. We have analyzed the expression profiles of various Notch liagnds in 779 breast cancer patients in GEO database and found that the expression of Jagged2 among all five ligands is most significantly correlated with the overall- and metastasis-free survival of breast cancer patients. The results of our immunohistochemical (IHC) analysis for Jagged2 in 61 clinical samples also revealed that both Jagged2 and Notch signaling were strongly up-regulated at the hypoxic invasive front. Activation of Jagged2 by hypoxia in tumor cells induced EMT and also promoted cell survival in vitro. Notably, a γ-secretase inhibitor significantly blocked Notch-mediated invasion and survival under hypoxia by promoting expression of E-cadherin and inhibiting AKT phosphorylation. Importantly, Jagged2 was also found to be up-regulated in bone marrow stroma under hypoxia and promoted the growth of cancer stem-like cells by activating their Notch signaling. Therefore, hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma plays a critical role in tumor progression and metastasis, and Jagged2 is considered to be a valuable prognostic marker and may serve as a novel therapeutic target for metastatic breast 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 1028. doi:10.1158/1538-7445.AM2011-1028
Abstract 1044: Role of autophagic mediators in the transition from endometriosis to endometriosis-associated ovarian cancers
Authors: Bauckman Kyle A. , Flores Idhaliz , Nanjundan Meera 
Published: June 2012

Abstract
Endometriosis, a common painful and inflammatory gynecological disease, has been proposed to contribute to the development of endometriosis-associated ovarian cancer, specifically the endometrioid and clear cell subtypes. The mechanism underlying this transition is unclear; however, many characteristics of endometriosis and endometrioid-ovarian cancer are similar with the exception of loss of cell cycle control. Autophagy, a survival mechanism which is activated in response to multiple stresses promotes tumorigenic development and may be an ideal target for therapy. To date, the role of autophagy in the development of endometrioid-ovarian carcinomas is unknown with the exception of attenuated mRNA levels of the autophagic marker, beclin-1, in an endometriosis-related condition. Since we have shown that SnoN/SkiL, a TGFβ co-transcriptional regulator, modulates autophagy in ovarian cancer cell lines, we propose that SnoN and/or autophagic mediators may be involved in the transition from endometriosis to ovarian cancer. Thus, we determined the basal expression levels of markers of TGFβ and autophagic pathways in primary and SV40 LTg immortalized endometriotic cells isolated from patients with endometriosis and compared their levels to endometrial/ovarian carcinoma cell lines. Cell lysates were prepared from confluent cultures of (1) five endometrial carcinoma cell lines (MFE296, MFE319, AN3-CA, KLE, and HEC-1A), (2) endometrioid-ovarian carcinoma cell line (TOV112D), (3) a clear cell carcinoma cell line (TOV21G), (4) three serous epithelial ovarian carcinoma cell lines (OVCAR8, HEY, and SKOV3), and (5) two primary (PNEs) as well as four SV40 LTg immortalized (INEs) normal endometriotic cells (derived from patients with endometriotic lesions). These were then assessed for protein expression levels of markers in various signaling pathways (autophagy, TGFβ, cell survival, and epithelial-mesenchymal transition) via western analysis and densitometric analysis. Relative to endometrial/serous epithelial ovarian carcinomas, PNEs and INEs expressed (1) low levels of oncogenes (EVI1, SnoN, and EGFR), (2) elevated levels of tumor suppressors (PTEN), (3) elevated levels of the EMT marker N-Cadherin, and (4) low levels of autophagic markers (i.e. ATG5, ATG7, and hVps34). Since we have observed marked differences in expression of autophagy and TGFβ signaling mediators, studies are ongoing to investigate the effects of knockdown and overexpression of ATGs and SnoN/SkiL in TOV112D and INEs, respectively, to determine their role in modulating this transition event.
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 1044. doi:10.1158/1538-7445.AM2011-1044
Abstract 1052: In vitro mechanism of action of AZD5363, a novel AKT inhibitor, in breast and prostate cancer cell lines
Authors: Greenwood Hannah , Crafter Claire , Davies Barry , Cosulich Sabina 
Published: June 2012

Abstract
AKT (protein kinase B) is a key regulator of the phosphoinositide-3-kinase signaling pathway and plays a key role in mediating signals for cell growth, survival and differentiation. This pathway is among the most commonly de-regulated pathways in human cancer and represents a key target for therapeutic intervention. Here, we describe the in-vitro mechanism of action of AZD5363, a potent small molecule inhibitor of AKT1, AKT2 and AKT3. We show that treatment of breast and prostate cancer cell lines with AZD5363 leads to inhibition of phosphorylation of a number of AKT substrates including PRAS40, GSK-3β and the downstream marker, P70S6K. In the BT474c cell line, &gt;90% inhibition of phosphorylation of PRAS40 was observed at 1uM and this effect was sustained for 24 hours. Inhibition of phosphorylation of 4E-BP1, a key regulator of protein translation, was also observed when treating cells with AZD5363. We demonstrate that inhibition of phosphorylation of 4EBP1 (Thr37/46) is associated with an induction of 4E-BP1 binding to the eIF4E-mRNA CAP complex within 1 hour of dosing with AZD5363, consistent with inhibition of CAP-dependent protein translation. Analysis of phenotypic endpoints indicates that AZD5363 is a potent inhibitor of proliferation in the majority of breast and prostate cell lines studied. In addition, in a subset of cell lines, treatment with AZD5363 was shown to induce a cytotoxic phenotype measured by a Sytox Green endpoint. In the BT474c cell line, 1uM AZD5363 inhibited phosphorylation of 4E-BP1 by 50% at 24 hours and induced 11% apoptosis at 72 hours. This data demonstrates that AZD5363 has profound effects on downstream effectors of the PI3K/AKT pathway consistent with that of an Akt inhibitor which results in an anti-proliferative, and in some cases cytotoxic, profile in breast and prostate cell lines. AZD5363 is currently in Phase I clinical trials.
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 1052. doi:10.1158/1538-7445.AM2011-1052
Abstract 1059: Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion
Authors: Gu Yumei , Lin Shuibin , Li Jian-Liang , Nakagawa Hiroshi , Chen Zirong , Tian Liang , Ucar Deniz A. , Shen Huangxuan , Lu Jianrong , Hochwald Steven N. , Kaye Frederic J. , Wu Lizi 
Published: June 2012

Abstract
Esophageal cancer is one of the most common malignancies and leading causes of cancer deaths worldwide. Esophageal squamous cell carcinoma accounts for the majority of esophageal cancers but in recent years the incidence of esophageal adenocarcinoma has increased dramatically, particularly in Western countries. Esophageal cancers are highly invasive and metastatic, which account for the high rate of cancer death. However, the exact molecular mechanisms that contribute to the initiation and progression of esophageal cancer remain unclear. LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome (PJS) and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that plays critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcriptional co-activators (CRTC) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated due to LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1-loss of function. Our study indicates that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression. Our data warrant future studies to understand the importance of LKB1 and CRTC signaling in esophageal cancers and to investigate CRTC activation as a target for cancers with LKB1 down-regulation.
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 1059. doi:10.1158/1538-7445.AM2011-1059
Abstract 1064: Pim serine/threonine kinases regulate the phosphorylation and function of eIF4B protein
Authors: Chen Jilong , Wang Jun , Yang Jianling 
Published: June 2012

Abstract
Eukaryotic initiation factor 4B (eIF4B) is a multidomain protein with a critical role in the initiation of protein synthesis, and has long been known as a hyperphosphorylated protein. It has been thought that function of eIF4B can be regulated by phosphorylation. The Pim family of Ser/Thr kinase, which is consisted of three members: Pim-1, Pim-2, and Pim-3, has been implicated in multiple cellular processes including cellular survival, anti-apoptosis and tumorigenesis. In this study, we identified eIF4B as a Pim kinase substrate. We found that Pim-1, Pim-2 but not Pim-3 can upregulate phosphorylation levels of eIF4B on Ser406 and Ser422 using 293T cell system, while kinase-dead mutants of Pim-1 or Pim-2 significantly inhibit phosphorylation of eIF4B. Furthermore, in vitro kinase assay revealed that Pim-1 kinase can directly phosphorylate eIF4B on Ser422. As expected, we found that Pim-1 kinase directly bound to eIF4B using GST-pull down assay and co-immunoprecipitation experiments. Interestingly, levels of eIF4B protein in v-Abl transformants treated with the Abl kinase inhibitor imatinib decreased markedly, indicating that expression of eIF4B is Abl kinase dependant. Our results suggest that Pim kinases regulate cellular processes via phosphorylating downstream eIF4B, and thereby alter the function of eIF4B in v-Abl transformants. Together, these data possibly provide new insights into molecular mechanisms of Abl oncogene-mediated cellular transformation.
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 1064. doi:10.1158/1538-7445.AM2011-1064