bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5105: Cyclosporin A and Cannabinoids induce autophagy-associated cell death in malignant glioma cells through inhibition of mTOR/S6K1 pathway
Authors: Ciechomska Iwona , Ellert-Miklaszewska Aleksandra , Kaminska Bozena 
Published: February 2011

Abstract
Malignant gliomas, the most common and aggressive primary brain tumors, account for more than 40% of all central nervous system (CNS) neoplasms. Gliomas are highly resistant to available therapies (radiation, chemiotherapy) that induce apoptosis (type I programmed cell death). Autophagy is a self-digestion process important for cell survival during starvation but functioning also as an alternative death mechanism under certain conditions (type II programmed cell death). Autophagy is negatively regulated by mammalian target of rapamycin (mTOR) and can be induced by its inhibitor, rapamycin. Using a panel of glioma cell lines bearing mutations in TP53 or PTEN we have demonstrated that cyclosporin A (CsA, an immunophilins/calcineurin inhibitor) and synthetic cannabinoids (counterparts of marijuana active ingredient THC) inhibit growth of glioma cells in vitro and induce cell death with apoptotic features. However, CsA- and cannabinoids-induced death was accompanied by the appearance of numerous cytoplasmic vacuoles, therefore, we investigated whether and to what extent autophagy contributes to drug-induced cell death of human malignant glioma cells. Upon CsA and cannabinoids treatment several features characteristic of autophagy were observed: formation of the acidic vesicular organelles, increase in punctuate GFP-LC3 (microtubule-associated protein light-chain 3) and LC3-II accumulation. All of the drugs affected mTOR signaling pathway in glioma cells decreasing phosphorylation of 4E-BP1 (eukariotic initiation factor 4E binding protein 1), p70-S6 kinase 1 and its downstream target molecule S6 ribosomal protein. Our results demonstrate that CsA and synthetic cannabinoids induce some features of apoptosis and autophagy-associated cell death in malignant glioma cells via inhibition of mTOR/S6K1 pathway. We are currently investigating the role of autophagy in dying cells using pharmacological and genetic inhibition of autophagy.
Studies supported by grant N N301 092036 from The Polish Ministry of Science and Higher Education.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5105.
Abstract 5106: Autophagy in malignant melanoma and breast carcinoma
Authors: Lazova Rossitza , Klump Vincent , Siddiqui Summar , Camp Robert , Pawelek John 
Published: February 2011

Abstract
We show here for the first time that autophagy is a remarkably common characteristic of malignant melanomas and breast carcinomas and is highly associated with metastasis and poor patient outcome. Autophagy is a cytoplasmic degradative process that in cancer can provide an energy source in times of nutrient deprivation. Interest in autophagy and cancer progression has increased markedly in recent years with reports that autophagy can be both a positive and negative survival factor for cancer cells. PURPOSE. The purpose of this study was to evaluate the prevalence of autophagy in melanoma and breast carcinoma, cancers from tissues of dissimilar lineages and functions. METHODS. Standard biopsies and tumor tissue microarrays containing core samples of melanoma (n = 342 cases) or breast carcinoma (n = 611 cases) were stained by immunohistochemistry for the autophagosome marker LC3B (microtuble-associated protein light chain 3B, detected with anti-LC3B polyclonal antibody ab48394, Abcam, Inc., Santa Cruz, CA). Autophagy was verified by the LC3B granular staining pattern and, in melanoma, by electron microscopy. RESULTS. In standard biopsies of melanoma, autophagic tumor cells emerged sporadically within the in situ tumor and were apparently the source of invasive cells in the dermis. For melanoma microarrays, 82% (107/130) of primary invasive melanomas and 90% (189/212) of lymph node metastases showed nearly uniform expression of autophagy with metastases showing increased LC3B staining intensity compared to primary tumors (p &lt; 0.0001). Similar results were obtained for breast carcinoma microarrays where 73% (447/611) of primary tumors showed high levels of autophagy and this correlated with poor patient outcome (p &lt; 0.001). Thus autophagy appears to be a constitutive metabolic state for a majority of malignant melanomas and breast carcinomas. The diverse origins and functions of these cells suggests that autophagy may be prevalent in other malignancies as well. Thus therapies targeting autophagy should be considered as a means to deprive cancer cells of an important energy source.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5106.
Abstract 5107: HDL and sphingosine-1-phosphate activate signal transducer and activator of transcription 3 in prostate cancer DU145 cells via ERK1/2 and S1P receptors
Authors: Sekine Yoshitaka , Suzuki Kazuhiro , Remaley Alan T. 
Published: February 2011

Abstract
(a) Introduction and Objective: Signal transducer and activator of transcription 3 (Stat3) has been implicated in the promotion of migration, invasion and growth of prostate cancer cells. Recently, HDL, which transports the bioactive lipid sphingosine-1-phosphate (S1P), was reported to activate Stat3 in cardiomyocytes and is a known mitogen for several cell types. S1P acts by binding to several G protein-coupled receptors, namely S1P1, S1P2 and S1P3, which are expressed in prostate cancer cell lines. Androgen deprivation therapy in men with prostate cancer leads to a significant increase of HDL-C, but the effect of HDL on prostate cancer is unknown. In this study, we examined the effect of HDL and S1P on Stat3 activation in prostate cancer cells and the involvement of ERK1/2, Akt, and S1P receptors in this process in 3 prostate cancer cell lines (PC-3, LNCaP and DU145). (b) Methods: We used HDL isolated from health volunteer men. Discordial reconstituted(r) HDL containing POPC and apoA-1, (POPC/A-1)rHDL or POPC, S1P and A-1, (POPC/S1P/A-1)rHDL were prepared by the cholate dialysis method. The phosphorylations of Stat3, ERK1/2 and Akt were detected by Western blot analysis. mRNA expressions of PC cells were evaluated by quantitative real-time PCR. Cell viability, migration and invasion were determined by MTS assay, would healing assay and matrigel invasion chamber assay, respectively. (c) Results: HDL increased a dose and a time dependent Ser727 phosphorylation of Stat3, but not Tyr705 in DU145 cells but not in the other two cell lines. S1P and (POPC/S1P/A-1)rHDL also induced the phosphorylation, but not rHDL made without S1P (POPC/A-1). They also induced DU145 cells proliferation, migration, invasion and phosphorylations of ERK1/2 and Akt. PD98059, a MEK inhibitor, and pertussis toxin, a Gi inhibitor, attenuated HDL-, S1P- and (POPC/S1P/A-1)rHDL-induced Stat3 phosphorylation, whereas LY294002, a PI3K inhibitor, had no effect. Concerning S1P receptors, S1P1 expression was much lower than S1P2 and S1P3 in DU145 cells. Both JTE013, a S1P2 antagonist, and VPC23019, a S1P1/S1P3 antagonist, attenuated HDL-, S1P- and (POPC/S1P/A-1)rHDL-induced Stat3 phosphorylations and cell migrations. (d) Conclusions: HDL was shown to induce Ser727 phosphorylation of Stat3 via its S1P constituent and involved both S1P2 and S1P3 receptors in DU145 cells. Moreover, ERK1/2 activation is involved in cell activation by HDL. These results suggest that the change in HDL plasma levels by androgen deprivation therapy HDL may alter prostate cancer growth and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5107.
Abstract 5110: Gallic acid induces apoptosis and autophagy in bladder cancer cell
Authors: Lee Huei-Jane , Ou Ting-Tsz , Lee Yung-Shu , Wang Chau-Jong 
Published: February 2011

Abstract
Flavonoid phytochemicals were studied on prevention or therapy in human malignancies including bladder cancer. Here we detected the effect of gallic acid (GA) in human bladder transitional cell carcinoma (TCC, TSGH-8301 cells). In MTT assay, TSGH-8301 cells treated with 30 or 40 μM of GA showed significant decrease of cell viability to about 40 or 20 %. To examine whether the cell death involving apoptosis, we used DAPI stain to observe nuclear condensation and agarose gel electrophoresis to detect DNA fragmentation. GA can cause bladder cell apoptosis. Additionally, the results from flow cytometric analysis showed that GA induced late stage of apoptosis and represented a dose-dependent manner, accompanied by the decrease of Bcl2 and increase of Bax. We also used acridine orange stain and evaluated the expression of LC3, microtubule-associated protein 1 light chain 3, a marker of autophagy, to detect whether GA can induce autophagy in bladder cancer cell. The results showed that GA possesses the ability to induce autophagy in bladder cancer cell in a dose-dependent manner. In conclusion, these results revealed that GA can induce apoptosis and autophagy in human bladder cancer cells. It also implies GA possesses the potential to treat bladder cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5110.
Abstract 5111: Metformin suppresses azoxymethane-induced colorectal carcinogenesis via activating AMP-activated protein kinase
Authors: Hosono Kunihiro , Endo Hiroki , Takahashi Hirokazu , Nakajima Atsushi 
Published: February 2011

Abstract
Metformin is widely used in the treatment of diabetes mellitus. Previous epidemiological reports suggest metformin reduce cancer incidence. Adenosine monophosphate-activated protein kinase (AMPK) is known to be activated by metformin, and inhibit the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role for protein translational machinery and cell proliferation. We examined the effect of metformin on the suppression of colorectal carcinogenesis in chemical carcinogen-induced models. Seven-week-old BALB/c mice i.p. injected with azoxymethane (AOM, 10 mg/kg) were treated with metformin (250 mg/kg/day) or without, for 6 weeks (for aberrant crypt foci (ACF) formation) or for 32 weeks (for polyp formation). We investigated colonic epithelial proliferation using the bromodeoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA) labeling indices. Western blot analysis was performed to elucidate the mechanism which affected colorectal carcinogenesis. Furthermore, to examine the indirect effect of metformin, the status of insulin resistance and serum lipid levels were assessed. Treatment with metformin significantly reduced the colon polyp and ACF formation, but there was no significant difference in body weight or glucose concentration. BrdU and PCNA indices decreased in mice treated with metformin. Western blot analysis revealed that phosphorylated mTOR, S6 kinase and S6 protein levels significantly decreased in mice treated with metformin. In conclusion, Metformin suppressed colonic epithelial proliferation via inhibition of the mTOR pathway by activation of AMPK. Metformin is already used daily as an antidiabetic drug, so it may be a safer and promising candidate for the chemoprevention of colorectal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5111.
Abstract 5113: Filopodial actin machinery cooperates with microtubules and vimentin intermediate filaments in the elongation of invadopodia
Authors: Schoumacher Marie , Louvard Daniel , Vignjevic Danijela 
Published: February 2011

Abstract
Invasive cancer cells breach the basement membrane (BM) using specialized protrusions, called invadopodia. Here, we found that the crossing of a native BM is a three-stage process: invadopodia form and perforate the BM; elongate into mature invadopodia; and then guide the cell towards the stromal compartment. We have studied the remodeling of cytoskeleton networks during invadopodia formation and elongation using ultrastructural analysis, spatial distribution of molecular markers and RNAi silencing of protein expression. We show that formation of invadopodia requires only the actin cytoskeleton, both filopodia- and lamellipodia-associated proteins. On contrary, using a novel in vitro assay, we demonstrate that elongation of invadopodia is mostly dependent on filopodial actin machinery, microtubules and vimentin intermediate filaments. These findings indicate that invadopodia form by assembly of dendritic/diagonal and bundled actin networks and then maturate by elongation of actin bundles together with the infiltration of microtubules and vimentin intermediate filaments.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5113.
Abstract 5114: SRC-1 Up-regulates Integrin α5 Expression and Enhances Breast Cancer Metastasis
Authors: Qin Li , Toneff Michael Joseph , Chen Xian , Wu Yelin , Li Yi , Xu Jianming 
Published: February 2011

Abstract
Steroid receptor coactivator-1 (SRC-1) is a member of the p160 SRC family, which also contains SRC-2 (TIF2/GRIP1) and SRC-3 (AIB1, p/CIP, ACTR, RAC3, TRAM-1). These molecules can interact with nuclear hormone receptors and certain other transcription factors to promote gene expression. In breast cancer, SRC-1 expression positively correlates with HER2 expression, disease recurrence and resistance to endocrine therapy. Our previous work has demonstrated that genetic ablation of SRC-1 in mice significantly suppresses breast cancer metastasis without affecting primary tumor initiation and growth in the MMTV-PyMT (polyoma middle T) mouse model. However, the mechanisms by which SRC-1 promotes breast cancer metastasis are unclear. To address the role of SRC-1 overexpression in breast cancer metastasis and mechanism, we generated MMTV-hSRC1 transgenic mice and found that MMTV-hSRC1 virgin mice exhibited normal mammary gland development. To take an advantage of the avian virus-mediated oncogene expression system, we crossed MMTV-hSRC1 mice to MMTV-tva mice and generated MMTV-hSRC1;MMTV-tva bi-transgenic mice. Intraductal injection of RCAS-PyMT avian viruses induced more metastasis in these bi-transgenic mice than in MMTV-tva mono-transgenic mice, suggesting that SRC-1 overexpression promotes lung metastasis. We also performed studies using MMTV-PyMT;SRC1−/− (KO) and MMTV-PyMT;SRC1+/+ (WT) cell lines derived from primary mouse mammary tumors. KO cells showed much lower migration and invasion capabilities than WT cells. KO cells also adhered much slowly to fibronectin and had reduced levels of active FAK, c-Src and Rac1. Mechanistic analyses revealed that SRC-1 was associated with a promoter region of integrin α5 with C/EBP and AP-1 binding sites and the integrin α5 gene might be a direct target of SRC-1. Accordingly, knockdown of integrin α5 in WT cells reduced cell adhesion and migration. Therefore, one of the pathways for SRC-1 to promote breast cancer cell migration and metastasis is to up-regulate integrin α5, leading to super activation of FAK, c-Src and Rac1. Our study provides a possibility to inhibit SRC-1-promoted breast cancer metastasis by targeting the integrin α5 function.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5114.
Abstract 5115: The role of Cdc42-interacting protein 4 (CIP4) in osteosarcoma tumorigenesis
Authors: Koshkina Nadezhda V. , Yang Ge , Kleinerman Eugenie S. 
Published: February 2011

Abstract
Osteosarcoma (OS) remains a devastating disease and requires better understanding of its biology for the development of novel therapeutic approaches. Tumor growth and metastases formation require an ability of cells to have a flexible cytoskeletal organization. Cdc42-interacting protein 4 (CIP4) is one of the scaffolding cytoskeleton-regulatory protein, whose role in tumors remains unknown. In the current study we investigated the role of CIP4 in OS tumorigenesis. We transfected highly aggressive mouse OS cells, DLM8 with the plasmid that downregulated expression of CIP4 protein (DLM8/shCIP4). We found that the growth rate of DLM8/shCIP4 clones was reduced by 30% when compared with non-transfected DLM8 cells or DLM8 cells transfected with control plasmid (DLM8/sh). When DLM8/shCIP4 cells were injected into mice subcutaneously they formed tumors that grew significantly slower than DLM8 or DLM8/sh control cells (p&lt;0.02). We also found that inhibition of CIP4 expression in DLM8 cells decreased their motility and invasion properties in vitro, indicating on its ability to impair metastases growth. Fluorescent immunostaining for actin in DLM8/shCIP4 cells revealed lower perinuclear actin stress filaments formation and lower actin bridge to the lipid bilayer of the lipid cell membrane when compared with wild-type DLM8 or DLM8/sh. We also observed that downregulation of CIP4 changed cell membrane morphology in DLM8 cells - they had less protrusions and smoother cell surface than control cells. All these findings indicate that CIP4 may also play a role in metastatic behavior of OS cells and needs further investigation.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5115.
Abstract 5116: p70 S6 kinase regulates the actin cytoskeleton in ovarian cancer cell motility by binding and cross-linking actin filaments
Authors: Ip Carman Ka Man , Wong Alice S. T. 
Published: February 2011

Abstract
p70 S6 kinase (p70S6K) is a downstream effector of phosphatidylinositol 3-kinase and is frequently activated in human ovarian cancer. Here we show for the first time that p70S6K functions in actin cytoskeleton reorganization responsible for the acquisition of invasiveness during tumor progression. Ectopic expression of active p70S6K in ovarian cancer cells induced dramatic reorganization of the actin cytoskeleton and promoted cell migration. Inhibition of p70S6K by siRNA or small molecule inhibitor resulted in diminished cell migration and actin cytoskeleton reorganization, confirming that these effects were p70S6K specific. By using cosedimentation and differential sedimentation assays, p70S6K was found to bind actin filaments, and was more effective in the presence than in the absence of phosphorylation. Importantly, purified p70S6K could be cosedimented with purified filamentous actin, indicating a direct association between p70S6K and actin. The response to p70S6K could be blocked with cytochalasin D, indicating that the binding of p70S6K to the cytoskeleton is mediated by actin. In addition, our results suggest that this is a functional interaction, because p70S6K was capable of generating specialized, actin-based cell morphologies via direct cross-linking activity. This bundling activity was confirmed by light scattering and electron microscopy. These results, in conjunction with our prior evidence that p70S6K regulates Rac and Cdc42 GTPases, suggest that p70S6K serves as an important regulator of the actin cytoskeleton, highlighting a role for p70S6K in the regulation of tumor progression and metastasis in ovarian cancer (This work is supported by Hong Kong Research Grants Council Grant HKU7599/05M to A.S.T.W.).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5116.
Abstract 5117: PKD1 suppresses filopodia formation and increases LIM Kinase 1 expression in prostate cancer cells
Authors: Biswas Md. Helal U. , Du Cheng , Zhang Chuanyou , Balaji K.C. 
Published: February 2011

Abstract
Introduction: We have previously demonstrated that transfection of PKD1 into highly metastatic C4-2 prostate cancer cells decreased cell motility. Filopodia are thin, actin-rich plasma-membrane protrusion that have an important role in cell motility and wound healing. Moreover, the initiation and elongation of filopodia depend on the precisely regulated polymerization, convergence and cross linking of actin filaments that are dynamically regulated by a variety of actin-binding proteins including Cofilin. However, Cofilin is inactivated by phosphorylation through the LIM kinase1 (LIMK1), a LIM-domain containing serine-threonine-tyrosine kinase, and activated by dephosphorylation through the Slingshot protein. In this study, we explored that PKD1 increased LIMK1 expression and suppressed filopodia formation with consequent effects on cell motility.
Methods: Phosphorylation of Cofilin as well as expression of GFP, PKD1-GFP and LIMK1 was confirmed by western blot analysis. Filopodia formation was detected by phalloidine staining. Wound healing assay was performed for evaluating the cell motility.
Results: To find out the role of PKD1 in LIMK1 regulation, we overexpressed PKD1 in PC3 cells followed by stimulation with phorbol 12-myristate 13-acetate (PMA) or Bryostatin-1, a PKD1 selective activator, and observed that the expression of LIMK1 was increased in dose dependent fashion compared to control. We also observed the phosphorylation of Cofilin was increased in PKD1 over expressing cells stimulated with PMA and Bryostatin-1 but not in control cells. Additionally, a number of filopodia were present in every GFP over expressing PC3 cells, whereas were completely absent in PKD1 over expressing PC3 cells. In addition, wound healing assay demonstrated that cell motility was suppressed by PKD1 over expression in PC cells compared to control.
Conclusions: Our data shows for first time that PKD1 modulates filopodia formation with increased expression of LIMK1 in PC cells. Additionally, we also found that PKD1 suppressed cell motility with regulation of Cofilin function that might play a role in suppression of metastasis. PKD1 suppressed filopodia formation by modulating LIMK1 expression a novel mechanism leading to altered motility in PC cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5117.