bluuebunny/crossref_metadata_2025_split huggingface dataset:
Curcumin Disrupts the Mammalian Target of Rapamycin-Raptor Complex
Authors: Beevers Christopher S. , Chen Long , Liu Lei , Luo Yan , Webster Nicholas J.G. , Huang Shile 
Published: January 2009

Abstract
Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Recently, we have shown that curcumin inhibits phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), two downstream effector molecules of the mammalian target of rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was designed to elucidate the underlying mechanism. We observed that curcumin inhibited mTORC1 signaling not by inhibition of the upstream kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor (compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKα. Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling. Finally, we identified that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate that curcumin may represent a new class of mTOR inhibitor. [Cancer Res 2009;69(3):1000–8]
GGAP2/PIKE-A Directly Activates Both the Akt and Nuclear Factor-κB Pathways and Promotes Prostate Cancer Progression
Authors: Cai Yi , Wang Jianghua , Li Rile , Ayala Gustavo , Ittmann Michael , Liu Mingyao 
Published: January 2009

Abstract
GGAP2/PIKE-A is a GTP-binding protein that can enhance Akt activity. Increased activation of the AKT and nuclear factor-κB (NF-κB) pathways have been identified as critical steps in cancer initiation and progression in a variety of human cancers. We have found significantly increased expression GGAP2 in the majority of human prostate cancers and GGAP2 expression increases Akt activation in prostate cancer cells. Thus, increased GGAP2 expression is a common mechanism for enhancing the activity of the Akt pathway in prostate cancers. In addition, we have found that activated Akt can bind and phosphorylate GGAP2 at serine 629, which enhances GTP binding by GGAP2. Phosphorylated GGAP2 can bind the p50 subunit of NF-κB and enhances NF-κB transcriptional activity. When expressed in prostate cancer cells, GGAP2 enhances proliferation, foci formation, and tumor progression in vivo. Thus, increased GGAP2 expression, which is present in three quarters of human prostate cancers, can activate two critical pathways that have been linked to prostate cancer initiation and progression. [Cancer Res 2009;69(3):819–27]
Prostaglandin E2 Stimulates Human Lung Carcinoma Cell Growth through Induction of Integrin-Linked Kinase: The Involvement of EP4 and Sp1
Authors: Zheng Ying , Ritzenthaler Jeffrey D. , Sun XiaoJuan , Roman Jesse , Han ShouWei 
Published: January 2009

Abstract
Cyclooxygenase-2–derived prostaglandin E2 (PGE2) stimulates tumor cell growth and progression. However, the mechanisms by which PGE2 increases tumor growth remain incompletely understood. In studies performed in non–small cell lung carcinoma (NSCLC) cells, we found that PGE2 stimulates the expression of integrin-linked kinase (ILK). ILK small interfering RNA (siRNA) inhibited the mitogenic effects of PGE2. In view of its perceived importance, we turned our attention to the mechanisms involved in PGE2-induced ILK expression and found that this effect was blocked by an antagonist of the PGE2 receptor subtype EP4 and by EP4 siRNA. Furthermore, we showed that PGE2 induction of ILK was associated with phosphorylation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt, which were abrogated by ILK siRNA. Transient transfection, gel mobility shift assays, and chromatin immunoprecipitation experiments showed that PGE2 induced ILK promoter activity and increased Sp1, although it had no effect on nuclear factor-κB and AP-2 DNA-binding activity. Blockade of Sp1 abrogated the effect of PGE2 on expression of ILK and promoter activity and on cell growth. In summary, our observations show that PGE2 increases NSCLC cell growth through increased ILK expression, which is dependent on EP4 signaling and on induction of Sp1 protein and Sp1 DNA-binding activity in the ILK promoter. These studies suggest a novel molecular mechanism by which PGE2 stimulates NSCLC cell growth and unveils a new molecular target for the development of therapies against NSCLC. [Cancer Res 2009;69(3):896–904]
Achaete-Scute Complex Homologue 1 Regulates Tumor-Initiating Capacity in Human Small Cell Lung Cancer
Authors: Jiang Tianyun , Collins Brendan J. , Jin Ning , Watkins David N. , Brock Malcolm V. , Matsui William , Nelkin Barry D. , Ball Douglas W. 
Published: January 2009

Abstract
The basic helix-loop-helix transcription factor achaete-scute complex homologue 1 (ASCL1) is essential for the development of normal lung neuroendocrine cells as well as other endocrine and neural tissues. Small cell lung cancer (SCLC) and non-SCLC with neuroendocrine features express ASCL1, where the factor may play a role in the virulence and primitive neuroendocrine phenotype of these tumors. In this study, RNA interference knockdown of ASCL1 in cultured SCLC resulted in inhibition of soft agar clonogenic capacity and induction of apoptosis. cDNA microarray analyses bolstered by expression studies, flow cytometry, and chromatin immunoprecipitation identified two candidate stem cell marker genes, CD133 and aldehyde dehydrogenase 1A1 (ALDH1A1), to be directly regulated by ASCL1 in SCLC. In SCLC direct xenograft tumors, we detected a relatively abundant CD133high-ASCL1high-ALDH1high subpopulation with markedly enhanced tumorigenicity compared with cells with weak CD133 expression. Tumorigenicity in the CD133high subpopulation depended on continued ASCL1 expression. Whereas CD133high cells readily reconstituted the range of CD133 expression seen in the original xenograft tumor, CD133low cells could not. Our findings suggest that a broad range of SCLC cells has tumorigenic capacity rather than a small discrete population. Intrinsic tumor cell heterogeneity, including variation in key regulatory factors such as ASCL1, can modulate tumorigenicity in SCLC. [Cancer Res 2009;69(3):845–54]
Suppression of cFLIP by Lupeol, a Dietary Triterpene, Is Sufficient to Overcome Resistance to TRAIL-Mediated Apoptosis in Chemoresistant Human Pancreatic Cancer Cells
Authors: Murtaza Imtiyaz , Saleem Mohammad , Adhami Vaqar Mustafa , Hafeez Bilal Bin , Mukhtar Hasan 
Published: January 2009

Abstract
Overexpression of cellular FLICE-like inhibitory protein (cFLIP) is reported to confer chemoresistance in pancreatic cancer (PaC) cells. This study was designed to investigate the effect of lupeol, a dietary triterpene, on (a) apoptosis of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) therapy–resistant PaC cells overexpressing cFLIP and (b) growth of human pancreatic tumor xenografts in vivo. The effect of lupeol treatment on proliferation and TRAIL/caspase-8/cFLIP machinery in PaC cells was investigated. Next, cFLIP-overexpressing and cFLIP-suppressed cells were tested for sensitivity to recombinant TRAIL therapy in the presence of lupeol. Further, athymic nude mice implanted with AsPC-1 cells were treated with lupeol (40 mg/kg) thrice a week and surrogate biomarkers were evaluated in tumors. Lupeol alone treatment of cells caused (a) decrease in proliferation, (b) induction of caspase-8 and poly(ADP-ribose) polymerase cleavage, and (c) down-regulation of transcriptional activation and expression of cFLIP. Lupeol was observed to increase the TRAIL protein level in cells. Lupeol significantly decreased the viability of AsPC-1 cells both in cFLIP-suppressed cells and in cFLIP-overexpressing cells. Lupeol significantly sensitized chemoresistant PaC cells to undergo apoptosis by recombinant TRAIL. Finally, lupeol significantly reduced the growth of human PaC tumors propagated in athymic nude mice and caused modulation of cFLIP and TRAIL protein levels in tumors. Our findings showed the anticancer efficacy of lupeol with mechanistic rationale against highly chemoresistant human PaC cells. We suggest that lupeol, alone or as an adjuvant to current therapies, could be useful for the management of human PaC. [Cancer Res 2009;69(3):1156–65]
A Long, Naturally Presented Immunodominant Epitope from NY-ESO-1 Tumor Antigen: Implications for Cancer Vaccine Design
Authors: Ebert Lisa M. , Liu Yu Chih , Clements Craig S. , Robson Neil C. , Jackson Heather M. , Markby Jessica L. , Dimopoulos Nektaria , Tan Bee Shin , Luescher Immanuel F. , Davis Ian D. , Rossjohn Jamie , Cebon Jonathan , Purcell Anthony W. , Chen Weisan 
Published: January 2009

Abstract
The tumor antigen NY-ESO-1 is a promising cancer vaccine target. We describe here a novel HLA-B7–restricted NY-ESO-1 epitope, encompassing amino acids 60-72 (APRGPHGGAASGL), which is naturally presented by melanoma cells. The tumor epitope bound to HLA-B7 by bulging outward from the peptide-binding cleft. This bulged epitope was not an impediment to T-cell recognition, however, because four of six HLA-B7+ melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX vaccine generated a potent T-cell response to this determinant. Moreover, the response to this epitope was immunodominant in three of these patients and, unlike the T-cell responses to bulged HLA class I viral epitopes, the responding T cells possessed a remarkably broad TCR repertoire. Interestingly, HLA-B7+ melanoma patients who did not receive the NY-ESO-1 ISCOMATRIX vaccine rarely generated a spontaneous T-cell response to this cryptic epitope, suggesting a lack of priming of such T cells in the natural anti–NY-ESO-1 response, which may be corrected by vaccination. Together, our results reveal several surprising aspects of antitumor immunity and have implications for cancer vaccine design. [Cancer Res 2009;69(3):1046–54]
The Plexin-A1 Receptor Activates Vascular Endothelial Growth Factor-Receptor 2 and Nuclear Factor-κB to Mediate Survival and Anchorage-Independent Growth of Malignant Mesothelioma Cells
Authors: Catalano Alfonso , Lazzarini Raffaella , Di Nuzzo Silvia , Orciari Silvia , Procopio Antonio 
Published: January 2009

Abstract
The semaphorins and their receptors, the neuropilins and the plexins, are constituents of a complex regulatory system that controls axonal guidance. Moreover, many types of tumor cells express various members of semaphorins and receptors, but the biological activities within tumor mass and the signal transduction mechanism(s) they use are largely unknown. Here, we show that in asbestos-related malignant pleural mesothelioma (MPM), Semaphorin-6D (Sema6D) and its receptor plexin-A1 are frequently expressed and trigger a prosurvival program that promotes anchorage-independent growth of MPM cells. Interestingly, the same response is also controlled by the tyrosine kinase receptors of vascular endothelial growth factor (VEGF) through a nuclear factor-κB (NF-κB)–dependent pathway. We found that in MPM cells, plexin-A1 and VEGF-receptor 2 (VEGF-R2) are associated in a complex. Moreover, the presence of Sema6D promotes the tyrosine phosphorylation of VEGF-R2 in a plexin-A1–dependent manner. This is necessary for basal and Sema6D-induced NF-κB transcriptional activity, and NF-κB mediates tumor cell survival. Expression of Sema6D and plexin-A1 is induced by asbestos fibers and overexpression of plexin-A1 in nonmalignant mesothelial cells inhibits cell death after asbestos exposure. This work identifies a new biological function of semaphorins in cancer cells and suggests the involvement of an undescribed survival pathway during MPM tumorigenesis. [Cancer Res 2009;69(4):1485–93]
Osteopontin Levels in an Asbestos-Exposed Population
Authors: Park Eun-Kee , Thomas Paul S. , Johnson Anthony R. , Yates Deborah H. 
Published: January 2009

Abstract
Purpose: Serum osteopontin levels in patients with malignant mesothelioma have been reported to be higher than in healthy subjects. This study assessed serum osteopontin levels in an asbestos-exposed population to test whether nonmalignant asbestos-related disorders could influence osteopontin levels.
Experimental Design: This cross-sectional study evaluated serum osteopontin levels in 525 male subjects. Subjects were classified into six different diagnostic groups, including asbestosis (n = 23), silicosis (n = 20), diffuse pleural thickening (n = 110), asbestosis and diffuse pleural thickening (n = 13), pleural plaques (n = 142), and healthy subjects with a history of asbestos exposure (n = 217).
Results: Mean serum osteopontin levels differed among the six groups (P &lt; 0.0001). Mean osteopontin values of the healthy individuals exposed to asbestos were significantly different from that of subjects with asbestosis (P &lt; 0.001) and diffuse pleural thickening (P &lt; 0.001). There was a significant difference in mean serum levels of osteopontin in healthy individuals exposed to asbestos (n = 217) compared with the group mean of all subjects with asbestos-related disorders (n = 288; P &lt; 0.0001).
Conclusions: Our results suggest that osteopontin levels are elevated in subjects with asbestos-related disorders without malignant mesothelioma. These data indicate that osteopontin, although reported to be useful for detecting malignant mesothelioma in asbestos-exposed individuals, may be influenced by nonmalignant processes.
Inhibition of cervical cancer cell growth by human papillomavirus virus–like particles packaged with human papillomavirus oncoprotein short hairpin RNAs
Authors: Bousarghin Latifa , Touze Antoine , Gaud Guillaume , Iochmann Sophie , Alvarez Eva , Reverdiau Pascale , Gaitan Julien , Jourdan Marie-Lise , Sizaret Pierre-Yves , Coursaget Pierre L. 
Published: January 2009

Abstract
Overexpression of human papillomavirus (HPV E6 and HPV E7) oncogenes in human cervical cells results in the development of cancer, and E6 and E7 proteins are therefore targets for preventing cervical cancer progression. Here, we describe the silencing of E6 and E7 expression in cervical carcinoma cells by RNA interference. In order to increase the efficacy of the RNA interference, HPV pseudovirions coding for a short hairpin RNA (shRNA) sequence were produced. The results indicated the degradation of E6 and E7 mRNAs when shRNA against E6 or E7 were delivered by pseudovirions in HPV-positive cells (CaSki and TC1 cells). E6 silencing resulted in the accumulation of cellular p53 and reduced cell viability. More significant cell death was observed when E7 expression was suppressed. Silencing E6 and E7 and the consequences for cancer cell growth were also investigated in vivo in mice using the capacity of murine TC1 cells expressing HPV-16 E6 and E7 oncogenes to induce fast-growing tumors. Treatment with lentiviruses and HPV virus-like particle vectors coding for an E7 shRNA sequence both resulted in dramatic inhibition of tumor growth. These results show the ability of pseudovirion-delivered shRNA to produce specific gene suppression and provide an effective means of reducing HPV-positive tumor growth. [Mol Cancer Ther 2009;8(2):357–65]
Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines
Authors: Clarke Michelle J. , Mulligan Evan A. , Grogan Patrick T. , Mladek Ann C. , Carlson Brett L. , Schroeder Mark A. , Curtin Nicola J. , Lou Zhenkun , Decker Paul A. , Wu Wenting , Plummer E. Ruth , Sarkaria Jann N. 
Published: January 2009

Abstract
Resistance to temozolomide and radiotherapy is a major problem for patients with glioblastoma but may be overcome using the poly(ADP-ribose) polymerase inhibitor ABT-888. Using two primary glioblastoma xenografts, the efficacy of ABT-888 combined with radiotherapy and/or temozolomide was evaluated. Treatment with ABT-888 combined with temozolomide resulted in significant survival prolongation (GBM12: 55.1%, P = 0.005; GBM22: 54.4%, P = 0.043). ABT-888 had no effect with radiotherapy alone but significantly enhanced survival in GBM12 when combined with concurrent radiotherapy/temozolomide. With multicycle therapy, ABT-888 further extended the survival benefit of temozolomide in the inherently sensitive GBM12 and GBM22 xenograft lines. However, after in vivo selection for temozolomide resistance, the derivative GBM12TMZ and GBM22TMZ lines were no longer sensitized by ABT-888 in combination with temozolomide, and a similar lack of efficacy was observed in two other temozolomide-resistant tumor lines. Thus, the sensitizing effects of ABT-888 were limited to tumor lines that have not been previously exposed to temozolomide, and these results suggest that patients with newly diagnosed glioblastoma may be more likely to respond to combined temozolomide/poly(ADP-ribose) polymerase inhibitor therapy than patients with recurrent disease. [Mol Cancer Ther 2009;8(2):OF407–8]
Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines
Authors: Squires Matthew S. , Feltell Ruth E. , Wallis Nicola G. , Lewis E. Jonathan , Smith Donna-Michelle , Cross David M. , Lyons John F. , Thompson Neil T. 
Published: January 2009

Abstract
Cyclin-dependent kinases (CDK), and their regulatory cyclin partners, play a central role in eukaryotic cell growth, division, and death. This key role in cell cycle progression, as well as their deregulation in several human cancers, makes them attractive therapeutic targets in oncology. A series of CDK inhibitors was developed using Astex's fragment-based medicinal chemistry approach, linked to high-throughput X-ray crystallography. A compound from this series, designated AT7519, is currently in early-phase clinical development. We describe here the biological characterization of AT7519, a potent inhibitor of several CDK family members. AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines, and the mechanism of action was shown here to be consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. Tumor regression was observed following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer xenograft models. We show that these biological effects are linked to inhibition of CDKs in vivo and that AT7519 induces tumor cell apoptosis in these xenograft models. AT7519 has an attractive biological profile for development as a clinical candidate, and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development. Studies described here formed the biological rationale for investigating the potential therapeutic benefit of AT7519 in cancer patients. [Mol Cancer Ther 2009;8(2):324–32]
Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib
Authors: Luster Troy A. , Carrell Jeffrey A. , McCormick Kathy , Sun David , Humphreys Robin 
Published: January 2009

Abstract
Mapatumumab and lexatumumab are fully human monoclonal antibodies that bind and activate human tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, respectively. These antibodies induce apoptosis in various tumor cell types, although the degree of sensitivity can vary from highly sensitive to completely resistant. Importantly, tumor cells that are partially or completely resistant to mapatumumab or lexatumumab can often be sensitized when treated in combination with chemotherapeutic drugs. In this regard, the proteasome inhibitor bortezomib has recently shown synergistic activity against established lymphoma cell lines and primary lymphomas when combined with mapatumumab and lexatumumab. Here, we report similar findings using a panel of human non-small cell lung cancer (NSCLC) cell lines. Specifically, we show that bortezomib rapidly induces sensitivity to mapatumumab and lexatumumab in NSCLC cell lines that are completely resistant to antibody alone and that bortezomib concentrations as low as 25 nmol/L sensitize NSCLC cells to the antibodies. Furthermore, bortezomib at the tested concentration has minimal effect on its own, indicating the combination generates synergistic cytotoxicity. Combination treatment induces activation of the caspase cascade and the effect of the combination is caspase dependent. Bortezomib treatment increases the intracellular levels of several important apoptosis regulators that may mediate enhanced sensitivity to mapatumumab and lexatumumab. These results suggest future evaluation of mapatumumab or lexatumumab in combination with bortezomib is warranted in NSCLC patients. [Mol Cancer Ther 2009;8(2):292–302]
A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development
Authors: Jimeno Antonio , Feldmann Georg , Suárez-Gauthier Ana , Rasheed Zeshaan , Solomon Anna , Zou Gang-Ming , Rubio-Viqueira Belen , García-García Elena , López-Ríos Fernando , Matsui William , Maitra Anirban , Hidalgo Manuel 
Published: January 2009

Abstract
There is an enormous gap between the antiproliferative and in vivo antitumor efficacy of gemcitabine in cell line-based models and its clinical efficacy. This may be due to insensitiveness of the precursor, cancer stem cell (CSC) compartment to cytotoxic agents. The hedgehog pathway is associated with CSC signaling and control. We used a direct xenograft model of pancreatic cancer and a two-stage approach was used to test the hypotheses that targeting CSC could increase the efficacy of gemcitabine. Tumors from a gemcitabine-sensitive xenograft were treated with gemcitabine first, and randomized, after tumor regression to continuing treatment with gemcitabine, a hedgehog inhibitor alone or in combination with gemcitabine. We tested markers described as associated with CSC such as CD24, CD44, ALDH, nestin, and the hedgehog pathway. After induction with gemcitabine, treated tumor showed an enrichment in CSC markers such as ALDH and CD24. Subsequently, a release from gemcitabine prompted a repopulation of proliferating cells and a decrease in such markers to equilibrate from pretreatment levels. Combined treatment with gemcitabine and cyclopamine induced tumor regression and decrease in CSC markers and hedgehog signaling. Cytoplasmic CD24 and ALDH were inversely and strongly associated with growth and were expressed in a minority of cells that we propose constitute the CSC compartment. Hedgehog inhibitors as part of a dual compartment therapeutic approach were able to further reduce tumor growth and decreased both static and dynamic markers of CSC. Direct tumor xenografts are a valid platform to test multicompartment therapeutic approaches in pancreatic cancer. [Mol Cancer Ther 2009;8(2):310–4]