bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5409: Cetuximab downregulates lactate dehydrogenase-A, leading to inhibition of glycolysis and reversal of the Warburg effect in HNSCC cells.
Authors: Lu Haiquan , Li Xinqun , Fan Zhen 
Published: August 2014

Abstract
Cetuximab is an anti-human epidermal growth factor receptor (EGFR) monoclonal antibody currently approved for treatment of patients with head and neck squamous cell carcinoma (HNSCC) in combination with conventional radiotherapy and chemotherapy. Previous studies showed that cetuximab downregulates the alpha subunit of the transcription factor hypoxia-inducible factor-1 (HIF-1α) through inhibition of EGFR-mediated downstream cell signaling and that downregulation of HIF-1α is required for cetuximab-induced antiproliferative effects; however, the underlying mechanism has not been established. In this study, we explored the mechanism from the perspective of cancer metabolism. HIF-1 plays a critical role in reprogramming cancer metabolism towards aerobic glycolysis (i.e., the Warburg effect), which is critically important for supplying cancer cells with the biomass needed for cell proliferation. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive cells in a HIF-1α downregulation-dependent manner. HNSCC cells with acquired resistance to cetuximab expressed a high level of HIF-1α and were highly glycolytic. Overexpression of a HIF-1α mutant conferred resistance to cetuximab-induced G1-phase cell cycle arrest, which could be overcome by knockdown of LDH-A expression. Addition of a small molecule LDH-A inhibitor markedly enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells, in which glycolysis is followed by oxidative phosphorylation in the mitochondria. These findings provide novel mechanistic insights into cetuximab-induced antitumor effects from the perspective of cancer metabolism and suggest novel strategies for enhancing the response of cancer patients to cetuximab therapy.
Citation Format: Haiquan Lu, Xinqun Li, Zhen Fan. Cetuximab downregulates lactate dehydrogenase-A, leading to inhibition of glycolysis and reversal of the Warburg effect in HNSCC cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5409. doi:10.1158/1538-7445.AM2013-5409
Abstract 5421: Sensitivity to dichloroacetate is determined by PDK expression.
Authors: Gang Bevan P. , Rooke Melissa , Mishra Sheenu , Dahlstrom Jane E. , Blackburn Anneke C. ,   Cancer Metabolism and Genetics Group.
Published: August 2014

Abstract
The Warburg effect occurs in 90% of tumours, where there is a high rate of glycolysis even in the presence of oxygen. This results in increased lactate production and reduced pyruvate oxidation. Dichloroacetate (DCA) is used clinically for congenital lactic acidosis and can reverse the Warburg effect by inhibiting the pyruvate dehydrogenase kinases (PDKs), activating pyruvate dehydrogenase thus promoting oxidative metabolism of pyruvate. The PDKs have different sensitivities towards DCA inhibition (PDK2&gt;PDK4&gt;PDK1&gt;&gt;PDK3). We have investigated the effects of DCA on cancer growth in vivo and in vitro, and examined the expression of the PDK isoforms to explain variation of cancer cell responses to DCA.
DCA halted the growth of established V14 mouse mammary tumours in vivo, but was ineffective against 4T1 mouse mammary tumours. In 8 human cancer cell lines of breast, colon, pancreatic and prostate origin, 5 mM DCA (48 hr) inhibited growth by 5-40% in vitro. Western blotting for expression of PDK isoforms revealed that the most sensitive T-47D cells expressed PDK2 and low levels of the other PDKs, whereas less sensitive cells expressed high levels of PDK1 and/or PDK3. In siRNA knockdown (kd) experiments, PDK3-kd in MCF7 cells (low DCA sensitivity, high PDK3 levels) increased sensitivity to DCA by 30%, while DCA did not further inhibit growth of PDK2-kd T-47D cells, confirming that sensitivity to DCA growth inhibition is determined by the PDK profiles. PDK1 & 3 are up-regulated in hypoxia, which may reduce the effectiveness of DCA. To the contrary, DCA increased apoptosis in hypoxia in MCF7 cells, suggesting that DCA can enhance effects of other stressors/drugs, an area of ongoing investigation.
Use of the PDK profiles to target DCA sensitive tumours will improve the outcomes of clinical trials using DCA that are currently underway
Citation Format: Bevan P. Gang, Melissa Rooke, Sheenu Mishra, Jane E. Dahlstrom, Anneke C. Blackburn, Cancer Metabolism and Genetics Group. Sensitivity to dichloroacetate is determined by PDK expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5421. doi:10.1158/1538-7445.AM2013-5421
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5426: Severe hypoxia drives the increased glucose demand in ascites carcinomas.
Authors: Li Xiao-Feng 
Published: August 2014

Abstract
Warburg reported his discovery in Ehrlich ascites carcinoma model, that in the presence of ample oxygen (21% or 150 mmHg O2), cancer cells utilize glucose by “aerobic glycolysis” (Warburg effect), apparently, ascites carcinoma had been assumed to be oxic. However, during past decade, growing evidences indicated that hypoxic cancer cells had evaluated radiolabeled glucose analog18F-FDG uptake than oxic cancer cell in vitro and in vivo. The objective of this study was to observe the oxygen status of ascites fluid and ascites carcinoma in mouse model of ascites carcinoma and its effect on glucose metabolism. Methods: Ascites carcinoma (floating single cells or clusters) and serosa tumors (attached to serosa) were induced by HT29, A549 or MDA-MB-231 cancer cells in the mouse peritoneal cavity. Ascites pO2 was measured using OxyLite systems in ketamine/xylazene anesthetized mice. Hypoxia status in ascites carcinoma and serosa tumors was tested by immunohistochemical visualization of exogenous hypoxia marker pimonidazole binding and HIF1alpha induced glucose transporter-1 expression. Glucose metabolism of was examine by 18F-FDG autoradiography. Effect of carbogen breathing (95% O2 & 5% CO2) on 18F-FDG uptake was investigated. Results: The pO2 of ascites was measured as low as 0.90mmHg (or 0.5% O2) in mice with HT29 ascites carcinomas. In all cell lines we tested, ascites carcinomas was evident 4-6 wk after cell inoculation, all ascites tumors were stained positive for pimonidazole and glucose transporter-1 (GLUT-1), indicating severe hypoxia. Hypoxia status in serosa tumors was heterogeneous and dependent on tumor size. 18F-FDG uptake was significantly higher in ascites and sub-millimeter serosa tumors than in larger ones (generally greater than 1 mm), the former was stained positive for pimonidazole and GLUT-1, but the latter was not. Carbogen breathing (2hrs) significantly reduced 18F-FDG uptake and pimonidazole binding in ascites carcinoma and submillimeter serosa tumors. GLUT1 expression was not affected. Conclusions: In mouse model of ascites carcinoma, ascites and floating ascites carcinoma are severely hypoxic which is in contradict with ample oxygen condition of Ehrlich ascites carcinoma model where “Warburg effect” derived from. Glucose utilization measured by 18F-FDG uptake is oxygen dependent in both ascites carcinoma and serosa tumors, this is unexplained sole by “aerobic glycolysis” of glucose metabolism, thus challenging Warburg effect theory.
This study was supported by Kentucky Lung Cancer Research Program Award
Citation Format: Xiao-Feng Li. Severe hypoxia drives the increased glucose demand in ascites carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5426. doi:10.1158/1538-7445.AM2013-5426
Abstract 5431: PPAR alpha independent effect of fenofibrate on glioblastoma cancer metabolism.
Authors: Wilk Anna M. , Zapata Adriana M. , Mullinax Jennifer R. , Wyczechowska Dorota D. , Reiss Krzysztof 
Published: August 2014

Abstract
Glioblastoma multiforme is the most common and aggressive primary brain tumor in adults. It is characterized by a rapid cell growth, CNS infiltration and is resistant to all known anticancer regimens. Therefore, development of effective therapies against these malignant brain tumors represents challenge for contemporary medicine. Anti-neoplastic potential of a common lipid-lowering drug, fenofibrate, is gaining a lot of attention, however, the precise mechanism of fenofibrate anti-cancer action remain to be elucidated. Fenofibric acid, which is an active metabolite of fenofibrate, is a potent agonist of peroxisome proliferator activated receptor alpha (PPARα), which transcriptional activity is expected to shift energy metabolism from glycolysis to fatty acid β-oxidation, therefore, it may be toxic to glycolytic tumor cells (Warburg effect). In parallel, to PPARα- dependent action, we have observed a strong PPARα- independent effect of fenofibrate on cancer cell energy metabolism, which was specific only to fenofibrate but not to fenofibric acid or to other PPARα agonists. We detected fenofibrate in mitochondrial membrane fractions of LN-229 cells treated with fenofibrate by using HPLC and subcellular fractionation. The accumulation of fenofibrate in mitochondrial membrane was accompanied by significant change in mitochondrial function, including loss of mitochondrial membrane potential, dramatic loss of oxygen consumption and lack of respiratory capacity measured as oxygen consumption rate (OCR). At the same time, fenofibrate increased the level of glycolysis (extracellular acidification rate, ECAR), possibly as compensation for impaired oxidative phosphorylation. In addition, fenofibrate-induced reduction of ATP levels triggered phosphorylation of AMPK and activation of autophagy.
In conclusion, our results demonstrate two seemingly independent mechanisms of fenofibrate anticancer action: PPARα-dependent, which shifts cell metabolism from glycolysis to fatty acid β-oxidation and PPARα-independent, which causes accumulation of fenofibrate in cell membranes and inhibition of oxidative phosphorylation. Both mechanisms counteract to make this drug very effective against Glioblastoma tumors causing inhibition of cell growth, survival and finally leading to massive apoptosis of these practically incurable tumors.
Citation Format: Anna M. Wilk, Adriana M. Zapata, Jennifer R. Mullinax, Dorota D. Wyczechowska, Krzysztof Reiss. PPAR alpha independent effect of fenofibrate on glioblastoma cancer metabolism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5431. doi:10.1158/1538-7445.AM2013-5431
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5433: Knockdown of the glycolytic enzyme PFKFB2 induces growth inhibition and enhances paclitaxel sensitivity in ovarian cancer cells.
Authors: Zhang Shu , Mao Weiqun , Sood Anil K. , Jennings Nicholas B. , Rodriguez-Aguayo Cristian , Lopez-Berestein Gabriel , Li Zong-Fang , Bast Robert C. , Le Xiao-Feng 
Published: August 2014

Abstract
Knockdown of certain glycolytic enzymes can affect ovarian cancer cell growth and enhance sensitivity to paclitaxel. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2 (PFKFB-2) is the cardiac isoform of the most important glycolytic regulator, phosphofructokinase-2, From the TCGA database of &gt;300 ovarian cancers, the PFKFB2 gene ranked in the top 33% of overexpressed genes and in the top 19% of genes with copy number gain. We found that PFKFB2 mRNA was upregulated in 10 of 12 ovarian cancer cell lines when expression of the gene was compared to that in normal ovarian epithelial cells in culture. Knockdown of PFKFB2 with siRNA markedly inhibited cell proliferation and increased paclitaxel sensitivity in p53 wild type ovarian cancer cell lines as demonstrated in short-term cytotoxicity and long-term clonogenic assays. Liposome encapsulated PFKFB2 siRNA significantly inhibited growth (P&lt;0.05) of human ovarian cancer xenografts in two ovarian cancer models (Hey A8 and A2780); even greater growth inhibition was observed when PFKFB2 siRNA treatment was combined with paclitaxel. Cell growth inhibition in cell culture was linked to G1 arrest and to a modest increase in apoptosis. Induction of p21Cip1 and p27Kip1 protein by PFKFB2 knockdown contributed to the G1 arrest, since silencing p21Cip1 and p27Kip1 dramatically reduced PFKFB2 knockdown-induced G1 arrest. PFKFB2 knockdown also modulated the expression of CDK2 and the phosphorylation of p27Kip1. Induction of p53 protein contributed to both PFKFB2 knockdown-induced G1 arrest and to apoptosis, since silencing p53 markedly alleviated PFKFB2 knockdown-induced G1 arrest and apoptosis. PFKFB2 knockdown inhibited expression of the ABC transporter family members ABCC4 and ABCG2 at the level of transcription, possibly contributing to enhanced paclitaxel retention and increased cytotoxicity after PFKFB2 knockdown. Taken together, these results suggest that PFKFB2 protein may regulate cell growth and sensitivity to paclitaxel by multiple mechanisms, particularly in p53 wild type ovarian cancers. As methods to deliver siRNA evolve in the clinic, PFKFB2 may provide a novel target for enhancing sensitivity to paclitaxel-based chemotherapy in patients with low grade serous ovarian cancer where p53 function remains intact.
Citation Format: Shu Zhang, Weiqun Mao, Anil K. Sood, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Zong-Fang Li, Robert C. Bast, Xiao-Feng Le. Knockdown of the glycolytic enzyme PFKFB2 induces growth inhibition and enhances paclitaxel sensitivity in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5433. doi:10.1158/1538-7445.AM2013-5433
Abstract 5436: Oct4 interaction with Hmgb2 regulates Akt signaling and the pluripotent gene expression signature.
Authors: Campbell Pearl A. , Stewart David J. , Rudnicki Michael A. 
Published: August 2014

Abstract
Akt signaling impacts multiple cellular functions associated with the hallmark characteristics of pluripotency such as cell cycle progression, cell growth, and enhanced cellular survival. Constitutive Akt activation promotes the pluripotent state and has also been implicated in several forms of cancer. Recent studies have suggested that while Akt activation may be a positive factor, the active nuclear form of Akt is associated with poor prognosis for many cancers, including lung cancer. Here, we describe a novel transcriptional regulatory feedback loop between Oct4, Hmgb2, and Akt. We show that Akt signaling promotes Oct4 phosphorylation and stability. This maintains interaction with Akt, Hmbg2 and other members of the SET complex such as Nme1 and Set. Upon differentiation, when Akt is inactive, their decreased interaction is observed. A functional genomics approach was therefore employed to determine the relevance of Oct4 interaction with Hmgb2 in maintaining the pluripotent state. Despite its previously described role in Polycomb group recruitment and transcriptional repression in Drosophila, we find that Hmgb2 knockdown results in decreased Akt signaling and decreased expression of many Oct4 transcriptional targets including genes implicated in cell cycle regulation, DNA repair, chromatin structure, as well as the pluripotency regulators Oct4, Sox2, and Nanog. Taken together, our results suggest that Oct4, Hmgb2, and the SET complex participate in a PTM-dependent feed forward regulatory loop that promotes active Akt signaling and the pluripotent gene expression signature. Future work will be focused upon dissecting the role of this network in maintaining constitutive nuclear Akt activation and promoting the primitive epigenetic state found in cancer. These findings may provide insight into the role of Akt in lung cancer chemoresistance and suggest alternate targets for more efficacious treatment.
Citation Format: Pearl A. Campbell, David J. Stewart, Michael A. Rudnicki. Oct4 interaction with Hmgb2 regulates Akt signaling and the pluripotent gene expression signature. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5436. doi:10.1158/1538-7445.AM2013-5436
Abstract 5438: Gene expression profiles resulting from stable and transient loss of p53 mirrors its role in tissue differentiation.
Authors: Couture Oliver , Lombardi Eric , Davis Kendra , Hays Emily , Chandar Nalini 
Published: August 2014

Abstract
The tumor repressor gene, p53, is involved in a variety of cellular activities ranging from stress, differentiation and cell cycle regulation. In our previous studies we have shown p53’s transcription activating role to be important in osteoblast differentiation. There is still a debate in the literature as to whether p53 inhibits or promotes differentiation. We have found p53 heterozygous mice to show a p53 dependency on some bone marker gene expression while the same is absent in p53 null mice. This deficiency of p53 has also been shown to produce more osteosarcomas than a complete loss of p53. This suggests that the presence of p53 is able to modify the environment within pre osteoblasts based on its ability to regulate key bone specific genes. In the present study we compared changes in gene expression resulting after either a transient or stable reduction in p53. Accordingly we reduced p53 levels in C2C12 cells capable of both myoblast and osteoblast differentiation transiently, and compared the changes in gene expression of candidate genes to cells with stable p53 knockdown. Using a PCR array to assay p53 target genes, we have found differential expression profiles when comparing stable versus transient knockdown. As expected several of genes that were profoundly affected after transient p53 loss were related to apoptosis and cell cycle regulation. Stable p53 loss produced a greater change in MyoD and other transcription factors with tissue specific roles suggesting that long term effect of p53 loss affects tissue homeostasis to a greater degree than changes resulting from acute loss of p53. These differences in gene expression were also validated by measuring promoter activities of different pathway specific genes involved in differentiation. These studies suggest that an important role for p53 is context dependent, with a stable reduction in p53 expression profoundly affecting normal tissue physiology than its acute loss.
Citation Format: Oliver Couture, Eric Lombardi, Kendra Davis, Emily Hays, Nalini Chandar. Gene expression profiles resulting from stable and transient loss of p53 mirrors its role in tissue differentiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5438. doi:10.1158/1538-7445.AM2013-5438
Abstract 5439: Developmental checkpoint function of Δ40p53.
Authors: Zhang Piyan , Scrable Heidi 
Published: August 2014

Abstract
Δ40p53, an N-terminally truncated p53 isoform, is predominantly expressed in embryonic stem cells (ESCs) and during early post-implantation embryogenesis in the mouse. We have discovered that Δ40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs. Our studies revealed this isoform of p53 inhibits retinoic acid-induced differentiation and subsequent epithelial-mesenchymal transition (EMT). As ESCs differentiate, Δ40p53 cannot activate the expression of some important developmental genes, such as p21, FGF10, DKK1, lamin A and ZO-1, coincident with decreasing Erk signaling and an enhanced Wnt/β-catenin pathway. ChIP assays suggested that p21, FGF10 and ZO-1 are inhibited at the elongation step. To distinguish between the transcription regulation functions of full-length p53 and Δ40p53, we generated stable HeLa cell lines transfected with Flag-tagged p53 and Δ40p53. qPCR and ChIP assays confirmed that Δ40p53, but not full-length p53, represses gene elongation, with a concomitant decrease in acetylation of histone H4 and H3 in the promoter region. Our studies reveal that Δ40p53, but not p53, is able to block ESC differentiation by regulation of specific gene expression at the elongation step during mouse development.
Citation Format: Piyan Zhang, Heidi Scrable. Developmental checkpoint function of Δ40p53. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5439. doi:10.1158/1538-7445.AM2013-5439
Abstract 5453: YK-4-279 inhibits ETS-positive prostate cancer cell metastasis in a mouse xenograft model.
Authors: Rahim Said , Justvig Sarah , Hong Sung-Hyeok , Kong Yali , Brown Milton L. , Morrissey Colm , Toretsky Jeffrey A. , Uren Aykut 
Published: August 2014

Abstract
Chromosomal translocations involving the ETS family of transcription factors are found in a majority of prostate cancers, including the most clinically aggressive forms. These translocations produce a chimeric gene, which fuses the promoter region of an androgen responsive gene to the coding region of ETS factors, most frequently ETV1 or ERG. Over-expression of ETS factors in prostate cancer cells results in a more invasive phenotype. The high prevalence of these rearrangements, and their biological significance represents a novel therapeutic target for the treatment of prostate cancer.
We recently demonstrated that the small molecule YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here we present our findings in an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously injected with LNCaP and PC-3 xenografts. Mice were treated with YK-4-279 and its effect on primary tumor size and lung metastasis was observed. YK-4-279 treatment resulted in reduced metastasis of the tumor from primary site to lungs. YK-4-279 also affected expression of ETV1 target genes such as MMP7 and MMP13. ETS fusion-negative PC-3 xenografts were unresponsive to YK-4-279.
Our results demonstrate that YK-4-279 decreases tumor growth and inhibits metastasis in fusion-positive prostate cancer cell xenografts. Therefore, YK-4-279 may have an impact on preventing metastasis in prostate cancer patients, which is a leading cause of death.
Citation Format: Said Rahim, Sarah Justvig, Sung-Hyeok Hong, Yali Kong, Milton L. Brown, Colm Morrissey, Jeffrey A. Toretsky, Aykut Uren. YK-4-279 inhibits ETS-positive prostate cancer cell metastasis in a mouse xenograft model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5453. doi:10.1158/1538-7445.AM2013-5453