bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1697: Pharmacological inhibition of ATM results in mitochondrial biogenesis in AMPK independent manner.
Authors: Khalil Hilal S. , Tummala Hemanth , DeCaris Laura , Zhelev Nikolai 
Published: August 2014

Abstract
The gene mutated in Ataxia telangiectasia termed Ataxia Telangiectasia Mutated (ATM) encodes for a Serine/Threonine protein kinase which functions at the core of signalling network responsible for DNA damage recognition and repair. Recent evidence has supported the role of ATM beyond DNA repair and has been shown to function in metabolic regulation and cellular homeostasis. Here, we show that ATM regulates mitochondrial biogenesis in MCF-7 and A549 cancer cell lines. Inhibition of ATM kinase activity with its specific inhibitor KU55933 (KU) both with and without DNA damage by Doxorubicin or Bleomycin resulted in evoked cytosolic Ca2+ ions leading to rapid, but sustained induction of mitochondrial biogenesis in these cell lines. This induction was independent of AMPK, a kinase previously shown to be involved in mitochondrial biogenesis as KU treatment resulted in downregulation of phospho AMPK. Moreover siRNA mediated knockdown of AMPK could not prevent KU dependent induction of mitochondrial biogenesis. Interestingly, KU treatment resulted in induction of Extracellular signal-regulated kinase(ERK) and CREB phosphorylation. Inhibition of ERK signalling by using MEK inhibitor U0126 disrupted KU dependent induction of mitochondrial biogenesis demonstrating the involvement of ERK signalling cascade in mitochondrial biogenesis upon ATM or AMPK inhibition. These results demonstrate that ATM maintains cellular homeostasis by regulating AMPK mediated mitochondrial biogenesis and that perturbation in this pathway by KU treatment causes a switch in mitochondrial biogenesis in ERK dependent manner. This study indicates cancer cell's fail-safe mechanism in maintaining its homeostasis by up-regulating mitochondrial biogenesis upon inhibition of ATM.
Citation Format: Hilal S. Khalil, Hemanth Tummala, Laura DeCaris, Nikolai Zhelev. Pharmacological inhibition of ATM results in mitochondrial biogenesis in AMPK independent manner. [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 1697. doi:10.1158/1538-7445.AM2013-1697
Abstract 1702: Metabolic heterogeneity of HER2-positive breast cancers.
Authors: Dennison Jennifer B. , Mills Gordon B. 
Published: August 2014

Abstract
Breast cancers are at least five molecularly distinct diseases with reported metabolic differences. Basal-like breast cancers are typically more glycolytic as compared to luminal-like breast cancers. However, HER2-positive breast tumors have variable FDG-PET maximum uptake values. We hypothesized that HER2-positive breast cancer cell lines would reflect the metabolic heterogeneity reported in breast cancer tumors. In the current study, a panel of HER2-positive breast cancer cell lines (N = 8) was profiled by their metabolic properties. To evaluate glycolytic dependency for ATP production, ATP-synthase dependent oxygen consumption rates were normalized to extracellular acidification rates using the Seahorse Bioscience XF analyzer. The glycolytic dependency was highly variable (12-fold range); ER-negative lines including AU565 and HCC1954 were the most glycolytic. Consistent with these results, HER2-positive/ER-negative cell lines produced more lactate compared to HER2-positive/ER-positive cell lines (1.5 versus 1.2 lactate produced/glucose consumed, p = 0.02). The glycolytic phenotypes of HER2-positive/ER-negative breast cancer cell lines were similar to that of basal-like breast cancer cell lines. For the HER2-positive lines, the highest rates of glutamine consumption were in ER-positive lines BT474 and HCC1419. Differential expression of mitochondrial glutaminase 2 (GLS2, p = 0.02), but not cytosolic glutaminase (GLS) or glutamine synthetase (GLUL), may contribute to higher rates of glutamine consumption by HER2-positive/ER-positive breast cancers. Consistent with higher rates of mitochondrial respiration, ER-positive/HER2-positive cells were also associated with higher expression of carbonic anhydrase 12 (CA12) and lower expression of the lactate transporter MCT1 (SLC16A1). Metabolic heterogeneity of HER2-positive cells was only evident in normoxic conditions. Per the “Pasteur effect,” all cell lines cultured under hypoxia (1% O2) were equally glycolytic (average = 1.8 lactate production/glucose consumption ratio) with correspondingly reduced rates of glutamine uptake. We conclude that the heterogeneity observed in FDG-PET may be influenced by fundamental metabolic differences between HER2-positive breast cancers, in particular, for well-oxygenated regions of the tumor.
Citation Format: Jennifer B. Dennison, Gordon B. Mills. Metabolic heterogeneity of HER2-positive breast cancers. [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 1702. doi:10.1158/1538-7445.AM2013-1702
Abstract 1705: Bioenergetic changes in glycolysis, Kreb's cycle, and glutaminolysis in pancreatic cells treated with mitochondria-targeted cationic drugs.
Authors: Cheng Gang , Zielonka Jacek , Joseph Joy , Kalyanaraman Balaraman 
Published: August 2014

Abstract
Human pancreatic ductal adenocarcinoma (PDAC) is an incurable and highly aggressive human cancer. Current chemotherapy provides a slight increase in survival. New therapeutic strategies to treat PDAC are desperately needed. In this study we used a relatively non-toxic mitochondria-targeted cationic nitroxide (Mito-CP) in combination with antiglycolytic agents (2-deoxyglucose, 2-DG) to selectively inhibit pancreatic cancer cell proliferation. We used high-throughput XF24 extracellular flux analyzer and mass spectrometry-based metabolomics approach to investigate cellular bioenergetics changes in pancreatic cancer cells (MiaPaCa-2 and Panc-1 cells). Results indicate that at nanomolar concentrations, Mito-CP alone potently inhibited proliferation of MiaPaCa-2 cells and synergized with 2-DG in inhibiting intracellular ATP levels. In the presence of glycolytic inhibitors, i.e. 2-DG or 3-bromopyruvate, Mito-CP exhibited enhanced toxicity in both pancreatic cell lines. LC-MS-based metabolomics studies indicate that Mito-CP inhibits Kreb's cycle metabolites (citric acid, cis-aconitic and isocitric acids) but significantly enhances intracellular glutamine, alpha-ketoglutarate, succinate, fumarate, and malate. This enhancement is abolished in glutamine-free media. We conclude that strategies to modulate bioenergetic metabolism with relatively non-toxic mitochondria-targeted nitroxides in combination with glycolysis or glutaminolysis inhibitors may provide a novel route for treating patients with PDAC with minimal toxic side effects.
Citation Format: Gang Cheng, Jacek Zielonka, Joy Joseph, Balaraman Kalyanaraman. Bioenergetic changes in glycolysis, Kreb's cycle, and glutaminolysis in pancreatic cells treated with mitochondria-targeted cationic drugs. [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 1705. doi:10.1158/1538-7445.AM2013-1705
Abstract 1715: Estrogen receptor β induces apoptosis through PUMA independent of p53 in prostate cancer cells.
Authors: Dey Prasenjit , Gustafsson Jan-Ake , Strom Anders M. 
Published: August 2014

Abstract
Estrogen receptor β1’s (ERβ1) expression is reduced during the progression of prostate cancer. In agreement with several studies indicating a tumor suppressive effect of ERβ, we find that expression of ERβ increases apoptosis in the prostate cancer cells. Cells expressing ERβ showed an increase in apoptotic cell population by TUNEL assay and flow cytometric analysis. In addition, cells expressing ERβ showed an increase in sub G1 cell population compared to the control cells. Also, ERβ decreases the expression of anti-apoptotic factor Bcl-2 and increases the expression of the pro-apoptotic factor PUMA. Regulation of PUMA was found to be independent of p53. Although phosphorylation of AKT was decreased by ERβ expression we could not see any reduction of phosphorylated FOXO3A, a known regulator of PUMA. On the other hand total mRNA and protein of FOXO3A increased indicating a direct regulation of FOXO3A by ERβ. Using non-transfected PC3 and LNCaP cells we could observe induction of FOXO3A and PUMA as well as apoptosis in response to added 3β-adiol, DPN or 8β-VE2 indicating that the small amount of ERβ expressed in these cell lines are sufficient to induce apoptosis in response to ERβ specific ligands. Overall, our study indicates an apoptotic action of ERβ and suggests that it can be advantageous to treat prostate cancer with ERβ agonist.
Citation Format: Prasenjit Dey, Jan-Ake Gustafsson, Anders M. Strom. Estrogen receptor β induces apoptosis through PUMA independent of p53 in prostate 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 1715. doi:10.1158/1538-7445.AM2013-1715
Abstract 1725: HDAC inhibition induces Bim expression and apoptosis in breast cancer cells undergoing paclitaxel or antiestrogen treatment.
Authors: Berning Aric , Eason Alexander , Gilley Nathan , Takhar Suchreet , ElShafey Sally , Thangaraju Muthusamy , Schoenlein Patricia V. 
Published: August 2014

Abstract
Paclitaxel functions by preventing microtubule degradation, leading to mitotic arrest and apoptotic death. Of particular interest, paclitaxel-induced death in breast cancer cells is dependent, in part, on the levels of BimEL, a pro-apoptotic member of the Bcl-2 family of proteins. In addition, our recent studies demonstrated that BimEL is required for 4-hydroxytamoxifen-induced apoptosis of estrogen receptor positive (ER+) MCF-7 breast cancer cells [Breast Cancer Res. 2012 Mar 19;14(2):R52]. In contrast, we demonstrated low-level BimEL expression in ER+ T47D breast cancer cells that do not undergo antiestrogen-induced apoptosis. Thus, low-level BimEL expression in ER+ breast cancer may predict a poor apoptotic threshold which ultimately would facilitate the development of acqured resistance to paclitaxel, as well as antiestrogen therapy. Based on the ability of HDAC inhibitors to increase the transcription of pro-apoptotic genes, we hypothesized that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would increase BimEL expression in T47D breast cancer cells and induce a robust apoptotic response to paclitaxel chemotherapy and antiestrogen treatment. In this study, we now demonstrate that SAHA does significantly up-regulate BimEL expression in T47D cells, as well as in MCF-7 cells. Concomitant with BimEL upregulation, SAHA sensitizes T47D and MCF-7 cells to paclitaxel-induced apoptosis. Similarly, SAHA sensitizes T-47D cells to antiestrogen-induced apoptosis, while augmenting the level of antiestrogen-induced apoptosis in MCF-7 cells. These studies indicate that the pro-apoptotic protein BimEL is required for SAHA-induced sensitization of breast cancer cells to paclitaxel and/or antiestrogen-induced apoptosis. Currently, siRNA studies are being conducted to determine if BimEL is a key death effector in response to SAHA treatment and if the increased death from SAHA and paclitaxel or SAHA and antiestrogens is synergistic or additive. Our results provide strong support for the use of HDAC inhibitors when designing novel combination therapies to reduce the emergence of acquired resistance in breast cancer cells undergoing chemo- or antihormonal therapy.
Acknowledgement: this work was supported by teh MCG foundation and NIHRO1 CA121438 to P.V.S.
Citation Format: Aric Berning, Alexander Eason, Nathan Gilley, Suchreet Takhar, Sally ElShafey, Muthusamy Thangaraju, Patricia V. Schoenlein. HDAC inhibition induces Bim expression and apoptosis in breast cancer cells undergoing paclitaxel or antiestrogen treatment. [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 1725. doi:10.1158/1538-7445.AM2013-1725
Abstract 1733: p62/sequestosome 1 regulates caspase-8 activation by the Bcl-2 antagonist ABT-263 to enable crosstalk between autophagy and apoptosis.
Authors: Huang Shengbing , Park Jae Myung , Yu Chunrong , Sinicrope Frank A. 
Published: August 2014

Abstract
Background: Autophagy and apoptosis regulate cancer cell viability in response to cytotoxic stress; however, the functional relationship between these processes is unclear. During autophagy, the multifunctional p62/sequestosome 1 protein shuttles ubiquitinated proteins to the lysosome. Previously, we found that ectopic p62 can promote chemotherapy-induced apoptosis. Since Bcl-2 can regulate both autophagy and apoptosis, we determined whether ABT-263-induced apoptosis is regulated by p62.
Methods: Human colorectal cancer cell lines (HCT116, DLD1) were incubated with ABT-263 (0-2 μM) and caspase cleavage (immunoblotting), caspase-8 activation (luminescence), apoptosis (annexin V labeling), and autophagy (localization of GFP-LC3 by confocal microscopy) were analyzed. Caspase-8 was suppressed by siRNA or using caspase-8-deficient Jurkat cells. P62 mutants were generated by site-directed mutagenesis. Caspase-8 self aggregation and colocalization with p62 were studied in cells with lentiviral mCherry-p62, transfected with a non-cleavable caspase-8 fused with fluorescent Venus proteins (BiFC).
Results: We demonstrate that ABT-263 induces autophagy and a caspase-8-mediated apoptosis, shown using caspase-8 siRNA or caspase-8-deficient cells. Regulation of this process by p62 was demonstrated by the ability of ectopic p62 expression to enhance apoptosis and caspase-8 activation that were disrupted by mutations at p62 functional domains. In contrast, p62 shRNA was shown to attenuate ABT-263-induced apoptosis. ABT-263 treatment enhanced binding between caspase-8 and p62, and triggered caspase-8 self aggregation that colocalized with p62, shown by Biomolecular Fluorescence Complementation (BiFC) assay using confocal microscopy. Consistent with ectopic p62, accumulation of p62 by the lysosomal autophagy inhibitors, chloroquine or bafilomycin A1, enhanced ABT-263-mediated caspase cleavage.
Conclusion: p62 can regulate caspase-8 self aggregation/activation by ABT-263 to enable crosstalk between autophagy and apoptosis.
Citation Format: Shengbing Huang, Jae Myung Park, Chunrong Yu, Frank A. Sinicrope. p62/sequestosome 1 regulates caspase-8 activation by the Bcl-2 antagonist ABT-263 to enable crosstalk between autophagy and apoptosis. [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 1733. doi:10.1158/1538-7445.AM2013-1733
Abstract 1736: Mitochondrial priming of apoptotic machinery in pancreatic cancer by BPM 31510 to enhance efficacy of chemotherapy.
Authors: Narain Niven R. , Walshe Tony E. , Lee Arleide , Ouro-Djoba Rakib , Mauro Lucia , Yunis Adel , Vishnudas Vivek K. , Sarangarjan Rangaprasad , Jimenez Joaquin J. 
Published: August 2014

Abstract
Recent evidence suggests that the cytotoxic effects of chemotherapy, specifically in cancer cells is a consequence of “pre-treatment priming” event wherein exposure to the chemotherapeutic agents pushes the cancer cells beyond an apoptotic threshold to effectuate cell death. (Letai, A et. al, Science. 2011 Nov 25;334 (6059) BPM 31510 is a ubidecarenone containing proprietary formulation that effectuates a metabolic switch from glycolysis towards enhanced mitochondrial oxidative phosphorylation resulting in the recapitulation of apoptosis in cancer. The current study was aimed at investigating whether pretreatment with BPM 31510 results in mitochondrial priming, thereby augmenting the cytotoxic effect of standard of care chemotherapeutic agents. The human derived pancreatic cancer cell line Mia-Paca-2 was subjected to either (a) pretreatment with BPM 31510 followed by co-treatment with gemcitabine or (b) co-treatment with BPM 31510 and gemcitabine. BPM 31510 exposure resulted in decreased cell proliferation rates that were significantly higher than gemcitabine alone in Mia-Paca-2 cell line. Pre-treatment with BPM 31510 augmented the cytotoxic potential of gemcitabine, a phenomenon that was also observed in the co-treatment regimen. In vivo pancreatic cancer model using Mia-Paca-2 cell lines were developed to further investigate the priming effect of BPM 31510. Results demonstrate that 1-week and 2-week pretreatment with intravenous BPM 31510 followed by gemcitabine results in improved survival in the pancreatic cancer model compared to the co-treatment regimen. The data demonstrates that addition of BPM
31510 synergizes the cytotoxic effect of gemcitabine in pancreatic cancer. In addition, pretreatment with BPM 31510 followed by gemcitabine treatment is associated with improved survival. Taken together, the data suggest that BPM 31510 may be a viable mitochondrial priming agent to sensitize cancer cells to the cytotoxic effects of gemcitabine in pancreatic cancer.
Citation Format: Niven R. Narain, Tony E. Walshe, Arleide Lee, Rakib Ouro-Djoba, Lucia Mauro, Adel Yunis, Vivek K. Vishnudas, Rangaprasad Sarangarjan, Joaquin J. Jimenez. Mitochondrial priming of apoptotic machinery in pancreatic cancer by BPM 31510 to enhance efficacy of chemotherapy. [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 1736. doi:10.1158/1538-7445.AM2013-1736
Abstract 1737: Pharmacological inhibition of fatty acid synthase regulates BH3-only proteins and sensitizes breast cancer cells to a small molecule Bcl-2/Bcl-xL inhibitor to induce apoptosis.
Authors: Venkatapoorna Chandra Mohan Kurapaty , Espinoza Ingrid , Kaufmann Scott H , Lupu Ruth 
Published: August 2014

Abstract
Fatty acid synthase (FASN), the key enzyme in de novo lipogenesis, is significantly upregulated and activated in many carcinomas, including breast cancer. Pharmacological inhibition of FASN induces apoptosis of FASN expressing cancer cells. However, the mechanism is still unclear. Inhibition of FASN in breast cancer cells induces a dose dependent increase in apoptotic cell death with a concomitant upregulation of the pro-apoptotic BH3-only proteins Noxa, Bim and Puma (mRNA and protein). Blockage of the BH3-only protein expression using specific small interfering ribonucleic acid (siRNA), significantly diminishes the apoptotic effect induced by the inhibition of FASN. Moreover, addition of palmitate, the end product of FASN, protects the cells from the proapoptotic effects of FASN inhibition by suppressing expression of Noxa, Bim and Puma. These data indicate that Noxa, Bim and Puma are essential for the apoptotic effect induced by the inhibition of FASN. Combination therapeutic regimens have received growing attention for the possibility of higher efficacy with reduced toxicity. Thus, we investigated the combinatorial effect of pharmacological inhibition of FASN and Bcl-2/Bcl-xL. While a small molecule Bcl-2/Bcl-xL inhibitor alone did not induce apoptosis, co-treatment of the small molecule Bcl-2/Bcl-xL inhibitor with a synthetic FASN inhibitor significantly surpassed the apoptotic effect of the synthetic FASN inhibitor alone. Accordingly, combined treatment of a FASN inhibitors and Bcl-2/Bcl-xL antagonists represents a new rational combination that merits further consideration in FASN overexpressing tumors.
Citation Format: Chandra Mohan Kurapaty Venkatapoorna, Ingrid Espinoza, Scott H Kaufmann, Ruth Lupu. Pharmacological inhibition of fatty acid synthase regulates BH3-only proteins and sensitizes breast cancer cells to a small molecule Bcl-2/Bcl-xL inhibitor to induce apoptosis. [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 1737. doi:10.1158/1538-7445.AM2013-1737
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1738: Multiparametric approaches to evaluate mitochondrial toxicity, oxidative stress and apoptosis in drug discovery studies.
Authors: Gillis Katherine , Clor Julie , Tran Kimvan , Khan Asima , Tyagarajan Kamala 
Published: August 2014

Abstract
Drug discovery and toxicity studies require access to methods and technologies that can provide comprehensive evaluation of the types of cellular impacts caused by anti-cancer compounds. In particular, there is growing emphasis on the study of mitochondrial toxicity at an early phase of compound evaluation and its relations to multiple cell death processes that include apoptotic cell death, caspase-independent death and autophagic processes. The study of oxidative stress and its relation to cell death pathways also provides insights into mechanism of cellular stress. In this study we have used multiparametric assays that correlate changes in mitochondria with different cell health parameters using plate-based microcapillary cytometry on guava easyCyte platforms. Compound screening studies were performed on Jurkats (suspension) and HeLa adherent cell lines using an array of over 80 compounds to study inter-relationships between mitochondrial perturbations and different cell health parameters. Compounds were evaluated for mitochondrial depolarization and relationship to apoptosis and cell death; mitochondrial perturbations with regard to caspase levels were also evaluated; and the parallel connection between mitochondrial superoxide stress and apoptosis was also studied. Our studies identified several hit compounds, examples of which included compounds like gambogic acid, thimerosal, camtothecin, antimycin A, staurosporine, celastrol and juglone which caused significant mitochondrial perturbation and apoptosis. In addition, compounds such as antimycin A and staurosporine caused significant oxidative stress. Simplified and rapid screening assays that provide information on multiple parameters of cellular stress and apoptosis can greatly benefit the identification of hit compounds and provide a more comprehensive understanding of the mechanism of compound toxicity.
Citation Format: Katherine Gillis, Julie Clor, Kimvan Tran, Asima Khan, Kamala Tyagarajan. Multiparametric approaches to evaluate mitochondrial toxicity, oxidative stress and apoptosis in drug discovery studies. [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 1738. doi:10.1158/1538-7445.AM2013-1738