bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3221: Anticancer effect of PUFAs is mediated by inhibition of polyisoprenylated methylated protein methyl esterase
Authors: Amissah Felix , Ayuk-Takem Lambert T. , Lamango Nazarius S. 
Published: August 2012

Abstract
Purpose: Polyisoprenylation is a set of secondary modifications involving proteins whose aberrant activities are implicated in cancers and macular degeneration. This process is essential for the activities of oncogenic proteins such as Ras. The terminal reversible step of polyisoprenylation pathway is catalyzed by an ester forming polyisoprenylated protein methyl transferase and polyisoprenylated methylated protein methyl esterase (PMPMEase). PUFAs share structural similarities with the polyisoprenyl groups and may interfere with polyisoprenylated protein metabolism. Methods: The effect of PUFAs on purified PMPMEase activity was studied. The inhibitory PUFAs were further evaluated on the viability of various cancer cell lines. The PMPMEase activity in the lysates of treated cells was analyzed in the presence or absence of COX-2/celecoxib. The mechanism of PUFAs-induced cell death was determined using a modified ethidium bromide and acridine orange (EB/AO) staining assay. Results: PUFAs such as arachidonic (AA), eicosapentaenoic and docosahexaenoic acids inhibited purified PMPMEase activity with Ki values of 0.12 to 3.7 µM. Enzyme kinetics analysis with PMPMEase revealed a 2- fold decrease in KM from 16.2 ± 1.34 to 8.60 ± 1.20 and 7.84 ± 1.02 μM in the presence of 10 μM AA or EPA, respectively. AA also induced the degeneration of various cancer cells at physiologically relevant concentrations (EC50 from 1 to 24 μM). The cellular PMPMEase activity also followed similar profiles to those of the cell viabilities in concentration-dependent studies. Treated degenerating cells displayed diminished PMPMEase activities. The inhibited PMPMEase activities in PUFAs-treated cells were restored by the addition of COX-2 but not in the presence of celecoxib. Conclusions: These data suggest that AA and other PUFAs, functioning through PMPMEase inhibition, may be involved in the regulation of cell proliferation. NSAIDs may thus owe their anticancer effects by protecting the PMPMEase- and cell proliferation-inhibiting PUFAs from COX-2 metabolism.
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 3221. doi:1538-7445.AM2012-3221
Abstract 3231: A small molecule inhibitor of glucose transporter 1 (Glut1) down-regulates glycolysis, induces cell cycle arrest, and inhibits cancer cell growth in vitro and in vivo
Authors: Liu Yi , Cao Yanyan , Zhang Weihe , Bergmeier Stephen , Qian Yanrong , Akbar Huzoor , Colvin Robert , Ding Juan , Tong Lingying , Wu Shiyong , Hines Jennifer , Chen Xiaozhuo 
Published: August 2012

Abstract
Increased dependence on glycolysis and glucose metabolism, known as the Warburg effect, is a near-universal hallmark of cancer. The functional and therapeutic importance of the effect has been increasingly recognized and glycolysis has become a new target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by using a glucose deprivation-like mechanism. Based on these and other results, we hypothesized that the compounds inhibit cancer growth by targeting Glut1 and they are efficacious in vivo as anticancer agents. Here we report that the representative and novel compound WZB117 not only inhibited cancer cell growth in multiple cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal (ip) injection of WZB117 at a dose of 10 mg/kg resulted in an over 70% reduction in the average size of xenografted tumor of human lung cancer A549 cell origin. Compound target study showed that WZB117 inhibited glucose transport in human red blood cells (RBC) and RBC-derived vesicles, both of which express Glut1 as their sole glucose transporter. Docking studies of WZB117-Glut1 interaction also demonstrate and support the binding of WZB117 to Glut1. Mechanism studies using multiple cancer cell lines revealed that treatment of WZB117 led to an induction of glycolytic enzymes, such as hexokinase, PKM2 and PGAM1; and then a decline of glycolysis as indicated by reduced lactate production with changes in Akt, AMPK and mTOR, protein factors in energy sensitive signaling pathways. These resulted in ER stress, followed by cell cycle arrest mediated through downregulation of cyclin E and Rb. Taken together, cell cycle arrest at G1/S phase plays major roles in the WZB117-induced inhibition of cancer cell growth while apoptosis is secondary. WZB117 can serve as a prototypic compound for further development of Glut1 inhibitors into novel anticancer therapeutics targeting glucose transport and glucose metabolism.
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 3231. doi:1538-7445.AM2012-3231
Abstract 3238: Frizzled-8 receptor is activated by the Wnt-2 ligant in non-small cell lung cancer
Authors: Bravo Dawn , Xu Zhidong , Kuchenbecker Kristopher , He Biao , Jablons David M. , You Liang 
Published: August 2012

Abstract
Introduction: Lung cancer is the leading cause of cancer-associated mortality throughout the world. We previously showed that the Wnt signaling pathway is aberrantly activated in lung cancer. In this report, we investigated the role of interactions between different Frizzled receptors and the Wnt-2 ligant in non-small cell lung cancer (NSCLC). Methods: Quantitative RT-PCR was used to measure expression of Frz-8 and Wnt-2 from fifty freshly resected lung tumors and matched normal lung tissue. A human dominant-negative Wnt-2 mutant (dnhWnt-2) was designed to target the interactions between Fzd-8 and Wnt-2 in vitro and in vivo. pTOPflash/pFOPflash luciferase activity assay was used to detect TCF/β-catenine transcription activity. Crystal violet staining assay was used to determine the colony formation. A mouse xenogrant model using A549 cells transfected with dnhWnt-2 vector or control vector was used to detect tumorigenic effects. Results: RT-PCR analysis showed that Wnt-2 overexpression is in correlation with overexpression of Fzd-8 in 45/50 (90%) tumor samples analyzed. Coexpression of the dnhWnt-2 construct together with Wnt-2 and Fzd8 expression vectors in 293T, 293 and A549 cells strongly reduced TCF-dependent transcriptional activity (TOPflash assay) as compared with cells transfected with control vectors. In lung cancer cell line A549, naturally overexpressing both Wnt-2 and Fzd8, the dnhWnt-2 construct induced cell death, inhibited cell proliferation. Results from colony formation assay showed 50% reduction in colonies formed from the dnhWnt-2 transfected cells as compared to control vector. A tumor xenograft model of A549 cells expressing the dnhWnt-2 mutant, demonstrated a marked reduction in tumor formation 43 days after cell inoculation (p&lt;0.02) with reduced Wnt downstream target gene expressions (Survivin, c-Myc, Dvl-3 and Cyclin- D1) compared to control tumors. Conclusion: This report demonstrated a novel interaction between Frz-8 receptor and Wnt-2 ligant in non-small cell lung cancer. Inhibition of this interaction may provide a new therapeutic avenue in targeting the Wnt pathway in lung 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 3238. doi:1538-7445.AM2012-3238
Abstract 3240: The Wnt secretion factor Evi/Wls/Gpr177 promotes glioma tumorigenesis
Authors: Augustin Iris , Goidts Violaine , Bongers Angelika , Kerr Grainne , Radlwimmer Bernhard , Hartmann Christian , Herold-Mende Christel , von Deimling Andreas , Reifenberg Guido , Boutros Michael 
Published: August 2012

Abstract
Malignant astrocytomas are highly aggressive brain tumors with poor prognosis. Despite multimodal therapy, including surgical resection followed by combined radio- and chemotherapy, the median survival of glioblastoma patients has remained as low as 12-14 months throughout the past decade. While a number of structural genomic changes and dysregulation of signaling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Recent evidence supports the involvement of canonical and non-canonical Wnt signaling in glioma development and malignant progression. Here, we show that the Wnt-specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas. Evi/Wls is a core Wnt signaling component and a specific regulator of pan-Wnt protein secretion, affecting both canonical and non-canonical signaling. We demonstrate that its depletion in glioma and glioma-derived stem-like cells led to decreased cell proliferation and apoptosis. Furthermore, Evi/Wls silencing in glioma cells reduced cell migration and the capacity to form tumors in vivo. We further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signaling. Taken together, our study identifies Evi/Wls as an essential regulator of glioma tumorigenesis, identifying a pathway- specific protein trafficking factor as an oncogene and offering novel therapeutic options to interfere with the aberrant regulation of growth factors at the site of production.
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 3240. doi:1538-7445.AM2012-3240
Abstract 3244: Compensatory function of the homologous proteins MIF and D-DT in regulation of AMPK-dependent metabolic-stress pathways in non-small cell lung carcinoma
Authors: Brock Stephanie Erin , Rendon Beatriz , Mitchell Robert 
Published: August 2012

Abstract
Macrophage migration inhibitory factor (MIF) is over-expressed in most solid malignancies and is important for many pro-tumorigenic pathways. Several studies reveal that genetic deletion or inhibition of MIF results in anti-cancer phenotypes, but these phenotypes are not nearly as profound as one would anticipate given its reported activities. We recently discovered that MIF's only related family member, D-dopachrome tautomerase (D-DT), functionally compensates for MIF-dependent promotion of angiogenic potential in non-small cell lung carcinoma (NSCLC). This finding not only provides an explanation for why MIF individual targeting has not provided more efficacious anti-cancer activities, but also suggests that therapeutic targeting of MIF and D-DT simultaneously may provide a highly effective and novel new class of anti-lung cancer pharmacologic agents. Here we present further evidence of the important cooperative function of these two homologous proteins in NSCLC cells. We reveal a strong collaborative effect of MIF and D-DT on the negative regulation of AMP-activated protein kinase (AMPK) activation. AMPK is phosphorylated by the tumor suppressor, LKB1, in response to metabolic stress, resulting in AMPK-dependent p53 activation and mTOR inhibition. We show that while siRNA-mediated knockdown of endogenous MIF or D-DT individually has modest effects on AMPK activation in NSCLC cells, combined knockdown of both MIF and D-DT results in a significant activation of AMPK-dependent regulation of p53 and mTOR pathways. Importantly, this re-activation of AMPK by MIF and D-DT occurs in LKB1 mutant NSCLC cell lines. In addition, overexpression of MIF or D-DT alone by adenoviral delivery causes a substantial reduction in p53 expression, with a dramatic increase in mTOR pathway activation. Our findings suggest that MIF and D-DT promote a unique and well conserved adaptation pathway that is usurped by the malignant cells in order to counter metabolic stress-induced, AMPK-dependent, tumor suppression. Because the LKB1 tumor suppressor locus is mutated in over 30% of NSCLC lesions rendering these tumors insensitive to AMPK-dependent growth suppression, the identification of unique AMPK agonists would be expected to have a tremendous impact on NSCLC disease management for clinicians. Taken together, simultaneous therapeutic targeting of both MIF and D-DT represents an innovative and clinically efficacious approach to re-activating metabolic stress-induced tumor suppression in NSCLC malignant lesions.
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 3244. doi:1538-7445.AM2012-3244
Abstract 325: Splice isoform switching: A new mechanism controlling EMT and breast cancer progression
Authors: Brown Rhonda L. , Reinke Lauren M. , Damerow Marin S. , Perez Denise , Chodosh Lewis A. , Yang Jing , Cheng Chonghui 
Published: August 2012

Abstract
Epithelial-mesenchymal transition (EMT) is a tightly regulated process that is critical for embryogenesis. When abnormally activated, EMT promotes cancer metastasis and recurrence. Here we show that splice isoform switching constitutes a novel mechanism that controls EMT. We identified a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) during EMT. This isoform switch to CD44s, which is regulated at the level of alternative splicing, is essential for cells to undergo EMT and is required for the formation of breast tumors that display EMT characteristics in mice. We demonstrate that the splicing factor ESRP1 controls the CD44 isoform switch and is critical for regulating the EMT phenotype. Furthermore, the CD44s isoform activates Akt signaling and inhibits cell death, providing a mechanistic link to a key pathway that drives EMT. Finally, CD44s expression is upregulated in high-grade human breast tumors and correlates with the level of the mesenchymal marker N-cadherin in these tumors. Together, these data suggest that regulation of CD44 alternative splicing causally contributes to EMT and breast cancer progression.
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 325. doi:1538-7445.AM2012-325
Abstract 3253: Bone morphogenetic proteins increase hepcidin in breast cancer cells
Authors: Clausen Kathryn A. , Di Xiumin , Torti Frank M. , Torti Suzy V. 
Published: August 2012

Abstract
Hepcidin is a systemic peptide hormone produced in the liver that regulates iron absorption and recirculation. Induction of hepcidin by inflammatory cytokines has been suggested to contribute to the anemia of inflammation and cancer. Our previous work has shown that synthesis of hepcidin is not confined to the liver, but is also observed in other tissues. In particular, we found that hepcidin is produced in mammary epithelial cells. Further, hepcidin levels increase in a subset of breast cancers, and increased synthesis of hepcidin is associated with poor prognoses in some breast cancer patients (Pinnix et al., 2010). In this work we sought to understand mechanisms regulating hepcidin synthesis in breast cancer, as well as the consequences of hepcidin upregulation. We demonstrate that treatment with bone morphogenetic proteins (BMPs) 2, 4, 6, or 7 results in hepcidin upregulation and concomitant Smad phosphorylation in breast cancer cells. The BMP7-induced hepcidin increase can be diminished by co-treatment of breast cancer cells with the BMP inhibitors, Wise or Noggin. We next assessed the consequence of hepcidin induction. Systemic hepcidin regulates iron by affecting the levels of the iron export protein, ferroportin. Extracellular hepcidin binds to ferroportin on the cell surface, initiating the internalization and degradation of ferroportin. This, in turn, decreases the ferroportin available to facilitate iron export, preventing iron efflux from the cell and increasing cellular iron retention. To test the functionality of this regulatory pathway in breast cancer, we used a hepcidin-specific antibody to deplete cultured breast cancer cells of extracellular hepcidin. We found that antibody-induced hepcidin depletion increased ferroportin protein levels, suggesting that hepcidin-mediated ferroportin regulation occurs in breast cancer cells. Consistent with this finding, we observed that breast cancer cells have increased hepcidin and decreased ferroportin relative to normal mammary epithelial cells. In all, these results raise the possibility that BMP signaling may control hepcidin expression in breast cells, decreasing ferroportin and increasing intracellular iron. The potential for hepcidin to alter iron availability to breast cancer cells on a paracrine level is a novel function for this key systemic iron regulator. Reference Z. K. Pinnix, L. D. Miller, W. Wang, R. D'Agostino Jr., T. Kute, M. C. Willingham, H. Hatcher, L. Tesfay, G. Sui, X. Di, S. V. Torti, F. M. Torti, Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis. Sci. Transl. Med. 2, 43ra56 (2010).
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 3253. doi:1538-7445.AM2012-3253
Abstract 3254: Cadherin-11 function is required for full neoplastic transformation by v-Src
Authors: Raptis Leda , Geletu Mulu , Arulanandam Rozanne 
Published: August 2012

Abstract
The signal transducer and activator of transcription-3 (Stat3) has emerged as an important signal transducer with a role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr-705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3, triggered by cadherin engagement. Stat3 activation was caused by a striking upregulation of the Rac GTPase and IL6, and induced downregulation of the p53 antioncogene, upregulation of anti-apoptotic genes and a potent survival signal. A large number of oncogenes such as vSrc activate the E2F transcription factor, found to be hyperactive in many cancers. E2F induces the expression of genes involved in cell division, as well as a number of receptor tyrosine kinases, that can, in turn, activate Stat3. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for survival signals. Since cadherin engagement activates Stat3, a potent survival signal, we examined the effect of downregulation of cadherin-11 upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Cadherin-11 knockdown through shRNA expression with a retroviral vector caused a dramatic reduction in Stat3 activity. At the same time, expression of vSrc in cadherin-11 knockdown cells failed to cause transformation; in the contrary, vSrc expression induced apoptosis. These data indicate that cadherin-11 is necessary for full neoplastic transformation of mouse fibroblasts by vSrc. This is especially remarkable because Src has been shown to have a negative effect upon, although not eliminate cadherin function, since Stat3 activity was, in fact increased in vSrc-expressing cells upon cadherin engagement. Therefore, it appears that the residual amounts of cadherin-11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis.
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 3254. doi:1538-7445.AM2012-3254
Abstract 3385A: Synergistic effect of purified components from Antrodia Cinnamomea Mycelia on targeting oral cancer stem cell
Authors: Chang Ching-Wen , Lo Jeng-Fan 
Published: August 2012

Abstract
Background: Cancer stem cells (CSCs), also termed as Cancer initiating cells (CICs), represent a rare subpopulation of cells, which are responsible for tumor growth. CICs such as oral cancer -cancer initiating cells (OC-CICs), are often resistant to either radio- or chemotherapy. Therefore, development of drug candidates that specifically target OC-CICs will be effective for future oral cancer therapy. Methods: In this study, we used the in vitro cell-based ALDH activity assay system, which has been demonstrated as a CICs marker, to screen for the active purified components from Antrodia Cinnamomea Mycelia extract (ACME), which can target OC-CICs. In combination with the active components from ACME that targeting OC-CICs, we evaluated the synergistic effect of above active components from ACMS on target oral cancer stem cells. Results: We first found ACME purified compounds (CH-190-WS-A and CH-190-WS-D) can significantly down regulate the ALDH activity of oral cancer cells or OC-CICs, respectively. Treatment of CH-190-WS-A and CH-190-WS-D significantly induced cell death and enhanced the differentiation capability of OC-CICs. Moreover, we found that treatment of CH-190-WS-A and CH-190-WS-D reduced the self-renewal ability, tumorigenic properties and stemness properties of OC-CICs in vitro. Additionally, treatment with CH-190-WS-A or CH-190-WS-D suppressed tumor growth of nude mice bearing tumor xenografts, respectively. Furthermore, treatment of CH-190-WS-D results in down-regulation of mTOR/PI3K/pAKT molecular mechanisms which play an important role in CICs. Whereas treatment of CH-190-WS-A inactivated Notch pathway, which can restore AKT activity then overcome cell death. Finally, combined treatment of CH-190-WS-D and CH-190-WS-A also dramatically caused cell death of OC-CICs through dual-pathway blockage. Conclusion: Our studies reveal combination of ACME purified components can target OC-CICs. Eventually, we can develop therapeutic protocol for alternative oral cancer treatment.
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 3385A. doi:1538-7445.AM2012-3385A