bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2441: mTOR complex 2 modulates glycosylation of CD147 via the hexosamine biosynthetic pathway
Authors: Wu Chang-Chih , Lynch Thomas , Moloughney Joseph , Navia Aixa , Ibironke Olufunmilola , Chou Po-Chien , Vega-Cotto Nicole M. , Zhang Sisi , Rabinowitz Joshua , Werlen Guy , Jacinto Estela 
Published: May 2015

Abstract
Cell surface proteins transduce extracellular signals into the cell to control metabolism and growth. In turn, their expression is linked to nutrient availability and other growth signals by mechanisms that are poorly understood. The mammalian target of rapamycin (mTOR) regulates cell growth and metabolism and is part of two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. We found that mTORC2 is involved in the processing and maturation of cell surface receptors such as CD147. CD147 is a highly glycosylated receptor that has been linked to tumor progression via its role in activating matrix metalloproteinases and maturation of lactate transporters. In breast cancer cells, CD147 glycosylation is highly sensitive to glucose starvation and mTOR inhibition. In mTORC2-disrupted cells CD147 is misprocessed and occurs predominantly in a low glycosylated form. CD147 misprocessing can be partly rescued by addition of exogenous UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway (HBP). However, UDP-GlcNAc cannot restore the abnormal growth and metabolism in mTORC2-disrupted cells due to defects in expression of other key metabolic enzymes in these cells. Our findings define a role for mTORC2 in regulating receptor glycosylation via the HBP and reveal a broader role for mTORC2 in controlling other biosynthetic pathways that become deregulated in cancer.
Citation Format: Chang-Chih Wu, Thomas Lynch, Joseph Moloughney, Aixa Navia, Olufunmilola Ibironke, Po-Chien Chou, Nicole M. Vega-Cotto, Sisi Zhang, Joshua Rabinowitz, Guy Werlen, Estela Jacinto. mTOR complex 2 modulates glycosylation of CD147 via the hexosamine biosynthetic pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2441. doi:10.1158/1538-7445.AM2014-2441
Abstract 2444: Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy
Authors: Xiao Lanbo , Hu Zhe-yu , Cao Ya 
Published: May 2015

Abstract
Our goal in this work was to illustrate the Epstein-Barr Virus (EBV)-modulated global biochemical profile and provide a novel metabolism-related target to improve the therapeutic regimen of nasopharyngeal carcinoma (NPC). We used a metabolomics approach to investigate EBV-modulated metabolic changes, and found that the exogenous overexpression of the EBV encoded latent membrane protein 1 (LMP1) significantly increased glycolysis. The deregulation of several glycolytic genes, including hexokinase 2 (HK2), was determined to be responsible for the reprogramming of LMP1-mediated glucose metabolism in NPC cells. The up-regulation of HK2 elevated aerobic glycolysis and facilitated proliferation by blocking apoptosis. More importantly, HK2 was positively correlated with LMP1 in NPC biopsies, and high HK2 levels were significantly associated with poor overall survival of NPC patients following radiation therapy. Knockdown of HK2 effectively enhanced the sensitivity of LMP1-overexpressing NPC cells to irradiation. Finally, c-Myc was demonstrated to be required for LMP1-induced up-regulation of HK2. The LMP1-mediated attenuation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis resulted in the stabilization of c-Myc. These findings indicate a close relationship between EBV and glycolysis in NPC. Notably, LMP1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells. Given the importance of EBV-mediated deregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Lanbo Xiao, Zhe-yu Hu, Ya Cao. Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2444. doi:10.1158/1538-7445.AM2014-2444
Abstract 2446: Signaling event of alcohol-induced deregulation of Pol III genes in breast cancer cells
Authors: Zhong Shuping , Zhang Qingsong , Shi Ganggang 
Published: May 2015

Abstract
Alcohol intake is consistently associated with an increased risk of breast cancer. Alcohol consumption is more pronounced in ER+ breast cancer cases than in ER- cases. However, its mechanism remains to be determined. We reported that alcohol induces Pol III gene (RNA polymerase III-dependent genes) transcription in vivo and in vitro. We continue to define novel and unexpected targets, MSK1 (mitogen- stress-activated protein kinase 1) and Brf1 (TFIIIB-related factor 1), in the alcohol-induced response. Our aim is to delineate the mechanisms regulating the processes of deregulation of Pol III genes, cell transformation and tumorgenesis through this alcohol-induced response. Brf1 specifically regulates Pol III gene transcription. Changes in Pol III gene and Brf1 expression tightly link to cell transformation and tumor formation. Alcohol-induced deregulation of Pol III genes may be fundamental to the development of breast cancer. We have reported that a) enhancement of Brf1 and Pol III gene expression is correlated with tumor formation in alcohol-fed mice; b) alcohol increases ERα activity to elevate Brf1 and Pol III gene expression; c) alcohol activates JNK1 to increase ERα and Brf1 expression; d) ethanol induces H3ph (histone H3 phosphorylation), e) H3ph elevates Brf1 expression. However, nothing is known about the role of MSK1 in transcription of Brf1 and Pol III genes. Analysis of signal event has revealed that ethanol markedly stimulates phosphorylation of MSK1 at serine 376 and threonine 581 in MCF-7 cells. Blocking MSK1 singling decreases cellular level of Brf1 expression and Pol III gene transcription. Further analysis indicates that MSK1 mediates ERα expression. Inhibition of MSK signaling decreases alcohol-induced ERE-Luc reporter activity. Repression of ERα expression by its siRNA reduces alcohol-induced anchorage-independent growth of MCF-7 cells. Our results have demonstrated that repression of MSK1 by its siRNA decreases colony formation of MCF-7 cells. Further analysis of ChIP assay indicates that ethanol treatment increases occupancy of ERα to Brf1 promoter. These results support the idea that alcohol activates MSK1 and enhances ERα and Brf1 expression resulting greater phenotypic changes. Together, our studies indicate that ethanol-induced MSK1 activation may play a critical role in alcohol-induced cell transformation and alcohol-associated ER+ breast cancer.
*: The project is supported by NIH grants AA017288 and AA021114 to Shuping Zhong
Citation Format: Shuping Zhong, Qingsong Zhang, Ganggang Shi. Signaling event of alcohol-induced deregulation of Pol III genes in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2446. doi:10.1158/1538-7445.AM2014-2446
Abstract 2457: Functional Study of DCC Gene in multiple myeloma mell lines
Authors: Rodrigues-Junior Dorival Mendes , Biassi Thais Priscilla , Carlin Viviane , Machado-Junior Joel , Vettore André Luiz 
Published: May 2015

Abstract
Functional Study of DCC Gene in Multiple Myeloma Cell Lines
ABSTRACT
INTRODUCTION: Multiple Myeloma (MM) is an incurable hematological malignancy characterized by multiorgan dysfunction as a result of bone marrow infiltration by malignant cells and the systemic damage of monoclonal circulating protein. Despite considerable progress in understanding MM biology, the molecular basis of this disease still remains open to debate. Previous data showed that DCC gene hypermethylation is significantly correlated with poor prognosis of MM patients. However, the involvement of DCC in the tumorigenesis process of MM remains unclear. PURPOSE: To better understand the role of DCC in this pathology through gene silencing in MM cell lines and evaluation of its interference in different tumorigenic processes. METHODS: The DCC gene expression was evaluated in three MM cell lines (RPMI-8226 and U266) and promoter methylation profile of this gene in the three cell lines was determined. The presence of DCC protein was confirmed by Western blotting (WB). The DCC expression was silenced by esiRNA and transfections were performed by electroporation. RESULTS: We detected the presence of aberrant methylation in DCC promoter in RPMI-8226, a cell line with undetectable expression of DCC. On the other hand, DCC was not methylated in U266, which present expression of DCC at mRNA and protein level. For this reason, DCC was silenced in U266 with esiRNA and its impact in the apoptosis, cell viability, proliferation and cell cycle processes was evaluated in this cell line.
Support by FAPESP
Citation Format: Dorival Mendes Rodrigues-Junior, Thais Priscilla Biassi, Viviane Carlin, Joel Machado-Junior, André Luiz Vettore. Functional Study of DCC Gene in multiple myeloma mell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2457. doi:10.1158/1538-7445.AM2014-2457
Abstract 246: Mammary cancer preventive activity of an extract of withania somnifera roots
Authors: Khazal kamel F. , Hill Donald , Grubbs Clinton J. 
Published: May 2015

Abstract
Mammary cancer preventive activity of an alcoholic extract of Withania somnifera (WS) roots was examined in female ErbB2+/- (MMTV/Neu) mice. The WS root extract was mixed with feed at a concentration of 750 mg/kg of diet. Mice treated with the root extract developed fewer mammary tumors relative to mice in the untreated group; after 310 days, mice in the treated group had an average of 1.62 tumors, and mice in the control group had 2.48, a reduction of 33% (p=0.1). Representative samples of the mammary tumors were examined histologically after staining with hematoxylin and eosin (H&E) and for proliferation (Ki67 and PCNA). For mammary tumors of control mice, sections stained with H&E showed high mitotic activity, whereas in tumors from treated mice, there was low mitotic activity. Labeling indices for Ki67 and PCNA markers in cancers of treated mice were 35% and 30% lower, respectively, than those of the control group. Expression of the cytokine CCL2 was 50% lower in cancers of the treated group. These results indicate that the root extract of WS reduces mammary tumor formation and tumor cell proliferation. Supported by grant U54 CA118948.
Citation Format: kamel F. Khazal, Donald Hill, Clinton J. Grubbs. Mammary cancer preventive activity of an extract of withania somnifera roots. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 246. doi:10.1158/1538-7445.AM2014-246
Abstract 2460: APC regulates COX-2 independent of Wnt signaling in breast cancer
Authors: VanKlompenberg Monica K. , Bedalov Claire , Prosperi Jenifer R. 
Published: May 2015

Abstract
Breast cancer is the leading cause of cancer-related death in non-smoking women, and the most commonly diagnosed cancer in women. The Adenomatous Polyposis Coli (APC) tumor suppressor gene is mutated or silenced by hypermethylation in 18-70% of sporadic breast cancers depending on subtype; however, the molecular mechanisms downstream of APC loss in the breast remain largely unexplored. While inactivation of APC most commonly leads to increased signaling through the Wnt/β-catenin pathway, there are multiple, less-investigated functions of APC, including regulation of GSK3β-mediated signaling, proliferation, epithelial polarity, cytoskeletal organization, and DNA repair. Given that restoration of tumor suppressors is a hurdle in treating tumors arising from loss of gene function, it is critical to investigate and understand the downstream signaling pathways involved in tumorigenesis. Our laboratory is particularly interested in investigating the effect of APC loss or mutation in breast cancer, and the complex Wnt-independent signaling downstream of APC loss in the breast. We previously demonstrated that Apc mutation accelerates the mouse mammary tumor virus-Polyoma middle T antigen (MMTV-PyMT) transgenic model of breast tumorigenesis independently of Wnt/β-catenin signaling. Interestingly, focal adhesion kinase (FAK)/Src/JNK signaling was up-regulated and required for the enhanced proliferation and squamous phenotype mediated by Apc mutation. Despite the lack of Wnt/β-catenin pathway activation, Apc-mutant mammary tumor cell lines demonstrated enhanced expression of Cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2), known to be important in triple-negative and inflammatory breast cancers, two aggressive breast cancer subtypes. While treatment with the Src inhibitor (PP2) decreases COX-2 protein expression, there is no effect on the level of phosphorylated JNK, indicating a non-linear signaling pathway. Consistent with this, treatment with an inhibitor of JNK (SP600125) has no effect on COX-2 expression. These data suggest that while Src activation downstream of Apc mutation enhances COX-2 in a Wnt-independent manner, the pathway does not travel through activation of JNK. Therefore, the mechanisms by which Apc mutation initiates this stream of events to enhance mammary tumorigenesis, and the contribution of COX-2 to the phenotypes acquired in Apc-mutant breast cancer remain unclear.
Citation Format: Monica K. VanKlompenberg, Claire Bedalov, Jenifer R. Prosperi. APC regulates COX-2 independent of Wnt signaling in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2460. doi:10.1158/1538-7445.AM2014-2460
Abstract 2465: p53-dependent and independent functions of Mieap
Authors: Nakamura Yasuyuki , Kamino Hiroki , Saito Yuri , Sano Hitoya , Arakawa Hirofumi 
Published: May 2015

Abstract
Mieap, a p53-inducible protein, plays a pivotal role in mitochondrial quality control (MQC) by repairing or eliminating unhealthy mitochondria1-4. To investigate physiological significance of the Mieap-regulated MQC, we generated and analyzed the Mieap-KO mice. (1) p53-dependent: Hypoxia induced Mieap expression and accumulation of lysosomal proteins within mitochondria in WT MEFs, but not Mieap-/- and p53-/- MEFs. Mieap-/- and p53-/- MEFs exhibited accumulation of oxidized mitochondrial proteins and increased ROS generation by unhealthy mitochondria under hypoxia, which enhanced cell migration and invasion. (2) p53-dependent: Mieap+/- / ApcMIN/+ mice displayed a shortening of the lifetime, compared to the ApcMIN/+ mice (average life-span: Mieap+/- / ApcMIN/+ mice vs ApcMIN/+ mice = 19.1 weeks vs 24.4 weeks), suggesting that Mieap deficiency may affect intestinal tumorigenesis. (3) p53-independent: Mieap was highly expressed in the midpiece, where the sperm mitochondria are localized, of the sperm in WT mice. This Mieap expression was independent on p53. Mieap-/- mice are fertile in vivo. However, in vitro fertilization of Mieap-/- sperm was severely impaired because of a failure of sperm motility. The oxidized proteins were dramatically accumulated in the midpiece of Mieap-/- sperm. These results, taken together, suggest that Mieap plays a crucial role in protection of the cell against oxidative stresses probably through its MQC function. This may also largely contribute to p53 tumor suppression.
1. Miyamoto Y et al. PLoS ONE 6: e16054, 2011
2. Kitamura N et al. PLoS ONE 6: e16060, 2011
3. Nakamura Y et al. PLoS ONE 7: e30767, 2012
4. Miyamoto T et al. Sci Rep 2: 379, 2012
Citation Format: Yasuyuki Nakamura, Hiroki Kamino, Yuri Saito, Hitoya Sano, Hirofumi Arakawa. p53-dependent and independent functions of Mieap. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2465. doi:10.1158/1538-7445.AM2014-2465
Abstract 2468: A p53 and microRNA-mediated pathway regulates mesenchymal stem cell differentiation
Authors: He Yunlong , Jiang Shunlin , Dubois Wendy , Ren Ling , Khanna Chand , Huang Jing 
Published: May 2015

Abstract
The tumor suppressor p53 plays important roles in bone density regulation and osteosarcoma suppression. However, the relationship between p53-mediated bone density regulation and osteosarcoma suppression is unclear mainly because the underlying molecular and cellular mechanisms are elusive. Here, we reported that p53 controls differentiation of mouse mesenchymal stem cells (mMSCs) in a cell cycle and apoptosis independent manner. The loss of p53 predisposes mMSCs towards osteogenic lineage but not adipogenic and chondrogenic lineages. This pro-osteogenic effect caused by p53 loss is associated with the up-regulation of Runt related transcription factor 2, a factor required for the osteogenic differentiation of mMSCs. Without extrinstic stress, studies show that p53 does not directly repress the transcription of Runt related transcription factor 2. Instead, it indirectly represses Runt related transcription factor 2 through activating microRNAs (miRs), which suppress Runt related transcription factor 2 at a post-transcriptional level. In osteosarcoma cells, the loss of p53 correlates with high levels of Runt related transcription factor 2 and the oncogene addiction of these cells to Runt related transcription factor 2. Together, our results discover a p53 and miR-mediated pathway regulating the differentiation of MSCs and this pathway is dysregulated in osteosarcoma cells. This lineage controlling role links the role of p53 in the osteogenic differentiation of MSC to its suppressive functions in osteosarcoma.
Citation Format: Yunlong He, Shunlin Jiang, Wendy Dubois, Ling Ren, Chand Khanna, Jing Huang. A p53 and microRNA-mediated pathway regulates mesenchymal stem cell differentiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2468. doi:10.1158/1538-7445.AM2014-2468
Abstract 2470: Cd177, a novel metastasis suppressor of breast cancer
Authors: Xie Qing , Borcherding Nicholas , Kolb Ryan , Zhang Weizhou 
Published: May 2015

Abstract
Mammary glands contain luminal and basal epithelial cells. We recently found that both luminal and basal epithelial cells can initiate malignant mammary tumors with forced ErbB2/Her2/c-Neu expression (referred to as luminal and basal tumor-initiating cells, respectively). Basal tumor-initiating cell (TIC)-derived tumors had a greater incidence and larger volume than luminal TIC-derived tumors. Transcriptomic analysis was performed to evaluate the underlying transcriptional difference between ErbB2-driven luminal and basal TIC-derived tumors. CD177 was found to be downregulated within basal TIC-derived tumors. CD177 is an important membrane glycoprotein on neutrophils and serves as a marker for myeloproliferative diseases. The role of CD177 in solid tumors is unknown. Our initial analysis revealed that loss of CD177 expression is linked to higher metastasis incidence and shorter survival in breast cancer patients, but not other diagnostic markers like estrogen-, progesterone-, or HER2-receptors. Silencing CD177 in 4T1 cells, a mouse mammary tumor cell line, led to a significant increase for colonic growth in soft agar and pulmonary metastasis in mice. Overexpressing CD177 in MCF7 cells, a human luminal mammary tumor cell line, resulted in a significant decrease for colonic growth in soft agar. We also found that genetic deletion of CD177 in female mice results in significantly increased Lineage-CD24+CD49fhi basal epithelial cells, the major tumor-initiating cells for ErbB2-induced breast cancer. Collectively, we identified a novel potential metastasis-suppressor for human breast cancer with important prognostic value. Future studies will involve in the mechanistic understanding of how CD177 regulates metastasis of breast cancer.
Citation Format: Qing Xie, Nicholas Borcherding, Ryan Kolb, Weizhou Zhang. Cd177, a novel metastasis suppressor of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2470. doi:10.1158/1538-7445.AM2014-2470
Abstract 2471: Direct down-regulation of eEF1A2 by Tumor suppressor p16INK4a inhibits cancer cell growth
Authors: Lee Mee-Hyun , Choi Bu Young , Cho Yong-Yeon , Kim Myoung O. , Kim Sung-Hyun , Lee Cheol-Jung , Song Ji Hong , Bode Ann M. , Dong Zigang , Surh Yong-Joon 
Published: May 2015

Abstract
The tumor suppressor protein p16INK4a is a member of the INK4 family of cyclin-dependent kinase (Cdk) inhibitors, which are involved in the regulation of the eukaryotic cell cycle. However, the mechanisms underlying the anti-proliferative effects of p16INK4a have not been fully elucidated. Using yeast two-hybrid screening, we identified the eukaryotic elongation factor (eEF)1A2 as a novel interacting partner of p16INK4a. eEF1A2 is thought to function as an oncogene in cancers. The p16INK4a protein interacted with all but the D2 (250-327 aa) domain of eEF1A2. Computational docking study predicted that D24/D131 residues of p16INK4a interacted with eEF1A2 and it was confirmed by pull-down assay with mutant p16INK4a (D24A/D131E). Ectopic expression of p16INK4a decreased the expression of eEF1A2 and inhibited cancer cell growth. Furthermore, suppression of protein synthesis by expression of p16INK4a ex vivo was verified by luciferase reporter activity. Microinjection of p16INK4a mRNA into the cytoplasm of Xenopus embryos suppressed the luciferase mRNA translation, whereas the combination of p16INK4a and morpholino-eEF1A2 resulted in a further reduction in translational activity. We conclude that the interaction of p16INK4a with eEF1A2, and subsequent downregulation of the expression and function of eEF1A2 is a novel mechanism explaining the anti-proliferative effects of p16INK4a.
Citation Format: Mee-Hyun Lee, Bu Young Choi, Yong-Yeon Cho, Myoung Ok Kim, Sung-Hyun Kim, Cheol-Jung Lee, Ji Hong Song, Ann M. Bode, Zigang Dong, Yong-Joon Surh. Direct down-regulation of eEF1A2 by Tumor suppressor p16INK4a inhibits cancer cell growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2471. doi:10.1158/1538-7445.AM2014-2471