MetaboList -May 2016

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Angiogenesis and metabolism
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Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients
Gabriela Jiménez-Valerio, Mar Martínez-Lozano, Nicklas Bassani, August Vidal, María Ochoa-de-Olza, Cristina Suárez, Xavier García-del-Muro, Joan Carles, Francesc Viñals, Mariona Graupera, Stefano Indraccolo, Oriol Casanovas
http://www.cell.com/cell-reports/fulltext/S2211-1247(16)30428-4

Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling
Elizabeth Allen, Pascal Miéville, Carmen M. Warren, Sadegh Saghafinia, Leanne Li, Mei-Wen Peng, Douglas Hanahan
http://www.cell.com/cell-reports/fulltext/S2211-1247(16)30442-9

Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy
Laura Pisarsky, Ruben Bill, Ernesta Fagiani, Sarah Dimeloe, Ryan William Goosen, Jörg Hagmann, Christoph Hess, Gerhard Christofori
http://www.cell.com/cell-reports/abstract/S2211-1247(16)30441-7

PERK mediates the IRES-dependent translational activation of mRNAs encoding angiogenic growth factors after ischemic stress
Céline Philippe , Alexandre Dubrac, Cathy Quelen, Aurore Desquesnes, Loic Van Den Berghe, Christèle Ségura, Thomas Filleron, Stéphane Pyronnet, Hervé Prats, Pierre Brousset, Christian Touriol
http://stke.sciencemag.org/content/9/426/ra44

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Amino acid metabolism
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Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells
Jonathan L. Coloff, J. Patrick Murphy, Craig R. Braun, Isaac S. Harris, Laura M. Shelton, Kenjiro Kami, Steven P. Gygi, Laura M. Selfors, Joan S. Brugge
http://www.cell.com/cell-metabolism/abstract/S1550-4131(16)30119-X

Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor
Abigail S. Krall, Shili Xu, Thomas G. Graeber, Daniel Braas and Heather R. Christofk
http://www.nature.com/ncomms/2016/160429/ncomms11457/full/ncomms11457.html

The EGF Receptor Promotes the Malignant Potential of Glioma by Regulating Amino Acid Transport System xc(—)
Kenji Tsuchihashi, Shogo Okazaki, Mitsuyo Ohmura, Miyuki Ishikawa, Oltea   Sampetrean, Nobuyuki Onishi, Hiroaki Wakimoto, Momoko Yoshikawa, Ryo  Seishima, Yoshimi Iwasaki, Takayuki Morikawa, Shinya Abe, Ayumi Takao,  Misato Shimizu, Takashi Masuko, Motoo Nagane, Frank B. Furnari, Tetsu  Akiyama, Makoto Suematsu, Eishi Baba, Koichi Akashi, Hideyuki Saya, and  Osamu Nagano
http://cancerres.aacrjournals.org/content/76/10/2954.abstract?etoc

Metabolic changes associated with methionine stress sensitivity in MDA-MB-468 breast cancer cells
Borrego S, Fahrmann  J, Datta R, Stringari C, Grapov D, Zeller M, Chen Y, Wang P, Baldi P, Gratton E, Fiehn O, Kaiser P
http://www.cancerandmetabolism.com/content/4/1/9/abstract

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Glucose metabolism
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ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy
Terytty Yang Li, Yu Sun, Yu Liang, Qing Liu, Yuzhe Shi, Chen-Song Zhang, Cixiong Zhang, Lintao Song, Pu Zhang, Xianzhong Zhang, Xiaotong Li, Tao Chen, Hui-Ying Huang, Xiadi He, Yi Wang, Yu-Qing Wu, Shaoxuan Chen, Ming Jiang, Canhe Chen, Changchuan Xie, James Y. Yang, Yan Lin, Shimin Zhao, Zhiyun Ye, Shu-Yong Lin, Daniel Tsun-yee Chiu, Sheng-Cai Lin
http://www.cell.com/molecular-cell/fulltext/S1097-2765(16)30059-4

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma
Talya L. Dayton, Vasilena Gocheva, Kathryn M. Miller, William J. Israelsen, Arjun Bhutkar, Clary B. Clish, Shawn M. Davidson, Alba Luengo,Roderick T. Bronson, Tyler Jacks, and Matthew G. Vander Heiden
http://genesdev.cshlp.org/content/30/9/1020.abstract?etoc

Hexokinase 2 is a determinant of neuroblastoma metastasis
Liat Edry Botzer, Shelly Maman, Orit Sagi-Assif, Tsipi Meshel, Ido Nevo, Ilana Yron and Isaac P Witz
http://www.nature.com/bjc/journal/v114/n7/full/bjc201626a.html

The platelet isoform of phosphofructokinase contributes to metabolic reprogramming and maintains cell proliferation in clear cell renal cell carcinoma
Jun Wang, Ping Zhang, Jie Zhong, Mingyue Tan, Jifu Ge, Le Tao, Yakui Li, Yemin Zhu, Lifang Wu, Jianxin Qiu,  and Xuemei Tong
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=8382

Histone deacetylase inhibitor–induced cancer stem cells exhibit high pentose phosphate pathway metabolism
Bisrat G. Debeb, Lara Lacerda, Richard Larson, Adam R. Wolfe, Savitri Krishnamurthy, James M. Reuben, Naoto T. Ueno, Michael Gilcrease,  and  Wendy A. Woodward
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=8631

Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma
F Ahmad, D Dixit, V Sharma, A Kumar, S D Joshi, C Sarkar and E Sen
http://www.nature.com/cddis/journal/v7/n5/abs/cddis2016117a.html

Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress.
Liu H, Kurtoglu M, León-Annicchiarico CL, Munoz-Pinedo C, Barredo J, Leclerc G, Merchan J, Liu X, Lampidis TJ.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=9263

Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma
Hidenari Hirata, Keishi Sugimachi, Hisateru Komatsu, Masami Ueda, TakaakiMasuda, Ryutaro Uchi, Shotaro Sakimura, Sho Nambara, Tomoko Saito, Yoshiaki Shinden, Tomohiro Iguchi, Hidetoshi Eguchi, Shuhei Ito, Kotaro Terashima, Katsumi Sakamoto, Masakazu Hirakawa, Hiroshi Honda, and Koshi Mimori
http://cancerres.aacrjournals.org/content/76/11/3265.abstract?etoc

Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy
Mahima Swamy, Shalini Pathak, Katarzyna M Grzes, Sebastian Damerow, Linda V Sinclair, Daan M F van Aalten, Doreen A Cantrell
http://www.nature.com/ni/journal/v17/n6/full/ni.3439.html

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Prostate cancer metabolism
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The metabolic co-regulator PGC1α suppresses prostate cancer metastasis
Veronica Torrano, Lorea Valcarcel-Jimenez, Ana Rosa Cortazar, Xiaojing Liu, Jelena Urosevic, Mireia Castillo-Martin, Sonia Fernández-Ruiz, Giampaolo Morciano, Alfredo Caro-Maldonado, Marc Guiu, Patricia Zúñiga-García, Mariona Graupera, Anna Bellmunt,Pahini Pandya, Mar Lorente, Natalia Martín-Martín, James David Sutherland, Pilar Sanchez-Mosquera, Laura Bozal-Basterra, Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, Antonio Berenguer, Nieves Embade, Aitziber Ugalde-Olano, Isabel Lacasa-Viscasillas, Ana Loizaga-Iriarte, Miguel Unda-Urzaiz, Nikolaus Schultz, Ana Maria Aransay,Victoria Sanz-Moreno, Rosa Barrio, Guillermo Velasco, Paolo Pinton, Carlos Cordon-Cardo, Jason W. Locasale, Roger R. Gomis & Arkaitz Carracedo
http://www.nature.com/ncb/journal/v18/n6/full/ncb3357.html

PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers
David P. Labbé, Noriko Uetani, Valérie Vinette, Laurent Lessard, IsabelleAubry, Eva Migon, Jacinthe Sirois, Jody J. Haigh, Louis R. Bégin, Lloyd C. Trotman, Marilène Paquet, and Michel L. Tremblay
http://cancerres.aacrjournals.org/content/76/11/3130.abstract?etoc

Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer
Akash K. Kaushik, Ali Shojaie, Katrin Panzitt, Rajni Sonavane, Harene Venghatakrishnan, Mohan Manikkam, Alexander Zaslavsky, Vasanta Putluri, Vihas T. Vasu, Yiqing Zhang, Ayesha S. Khan, Stacy Lloyd, Adam T. Szafran, Subhamoy Dasgupta, David A. Bader, Fabio Stossi, Hangwen Li, Susmita Samanta, Xuhong Cao, Efrosini Tsouko, Shixia Huang, Daniel E. Frigo, Lawrence Chan, Dean P. Edwards, Benny A. Kaipparettu, Nicholas Mitsiades, Nancy L. Weigel, Michael Mancini, Sean E. McGuire, Rohit Mehra, Michael M. Ittmann, Arul M. Chinnaiyan, Nagireddy Putluri, Ganesh S. Palapattu, George Michailidis & Arun Sreekumar
http://www.nature.com/ncomms/2016/160519/ncomms11612/full/ncomms11612.html

Oxidative phosphorylation and mitochondrial function differ between human prostate tissue and cultured cells
Bernd Schöpf, Georg Schäfer, Anja Weber, Heribert Talasz, Iris E. Eder, Helmut Klocker and Erich Gnaiger
http://onlinelibrary.wiley.com/doi/10.1111/febs.13733/abstract?campaign=woletoc

Molecular characterization of Gleason patterns 3 and 4 prostate cancer using reverse Warburg effect-associated genes
Georgescu I, Gooding R, Doiron R, Day A, Selvarajah S, Davidson C, Berman D, Park P
http://www.cancerandmetabolism.com/content/4/1/8/abstract

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Mitochondria
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Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation
Yue Jin, Qingsong Cai, Anitha K. Shenoy, Sangbin Lim, Ying Zhang, Steve Charles, Miriam Tarrash, Xueqi Fu, Sushama Kamarajugadda, Jose G. Trevino, Ming Tan,  and  Jianrong Lu
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=7159

Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors
Gao Zhang, Dennie T. Frederick, Lawrence Wu, Zhi Wei, Clemens Krepler, Satish Srinivasan, Young Chan Chae, Xiaowei Xu, Harry Choi, Elaida Dimwamwa, Omotayo Ope, Batool Shannan, Devraj Basu, Dongmei Zhang, Manti Guha, Min Xiao, Sergio Randell, Katrin Sproesser, Wei Xu, Jephrey Liu, Giorgos C. Karakousis, Lynn M. Schuchter, Tara C. Gangadhar, Ravi K. Amaravadi, Mengnan Gu, Caiyue Xu, Abheek Ghosh, Weiting Xu, Tian Tian, Jie Zhang, Shijie Zha, Qin Liu, Patricia Brafford, Ashani Weeraratna, Michael A. Davies, Jennifer A. Wargo, Narayan G. Avadhani, Yiling Lu, Gordon B. Mills, Dario C. Altieri, Keith T. Flaherty, Meenhard Herlyn
http://www.jci.org/articles/view/82661

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Lipids
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Loss of Chromosome 8p Governs Tumor Progression and Drug Response by Altering Lipid Metabolism
Yanyan Cai, Jonathan Crowther, Tibor Pastor, Layka Abbasi Asbagh, Maria Francesca Baietti, Magdalena De Troyer, Iria Vazquez, Ali Talebi, Fabrizio Renzi, Jonas Dehairs, Johannes V. Swinnen, Anna A. Sablina
http://www.cell.com/cancer-cell/abstract/S1535-6108(16)30161-1

mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer
Yaqing Chen, Jianchang Qian, Qun He, Hui Zhao, Lourdes Toral-Barza, Celine Shi, Xuesai Zhang, Jiang Wu,  and  Ker Yu
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=8279

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Nutrient sensing / starvation
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eIF4A inactivates TORC1 in response to amino acid starvation
Foivos‐Filippos Tsokanos, Marie‐Astrid Albert, Constantinos Demetriades, Kerstin Spirohn, Michael Boutros, and Aurelio A Teleman
http://EMBOJ.embopress.org/content/35/10/1058?etoc

Posttranscriptional Regulation of Gcr1 Expression and Activity Is Crucial for Metabolic Adjustment in Response to Glucose Availability
[yeast]
Munshi Azad Hossain, Julia M. Claggett, Samantha R. Edwards, Aishan Shi, Sara L. Pennebaker, Melodyanne Y. Cheng, Jeff Hasty, Tracy L. Johnson
http://www.cell.com/molecular-cell/fulltext/S1097-2765%2816%2930062-4

AMPK and PKA interaction in the regulation of survival of liver cancer cells subjected to glucose starvation
Anabela C. Ferretti, Facundo M. Tonucci, Florencia Hidalgo, Evangelina Almada, Maria C. Larocca, Cristián Favre
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=7404&pubmed-linkout=1

Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction
A R Hall, N Burke, R K Dongworth, S B Kalkhoran, A Dyson, J M Vicencio, G W Dorn II, D M Yellon and D J Hausenloy
http://www.nature.com/cddis/journal/v7/n5/abs/cddis2016139a.html

WITHDRAWN: Regulation of Pyruvate Kinase M Switch towards PKM1 by LKB1-AMPK Axis Tolerates Hypoglycemic Stress in Cancer Cells
Prakasam Gopinath, Rajnish Kumar Singh, Mohammad Askandar Iqbal, Ashu Bhan Tiku, and Rameshwar N. K. Bamezai
http://www.jbc.org/content/early/2016/05/13/jbc.M116.729079.abstract

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Hypoxia and HIFs
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Protein kinase A-dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1
John W. Bullen , Irina Tchernyshyov, Ronald J. Holewinski, Lauren DeVine, Fan Wu, Vidya Venkatraman, David L. Kass, Robert N. Cole, Jennifer Van Eyk, Gregg L. Semenza
http://stke.sciencemag.org/content/9/430/ra56

Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1α: a novel approach for inhibiting angiogenesis in hepatocellular carcinoma
Julia Herzog, Sandra M. Ehrlich, Lisa Pfitzer, Johanna Liebl, Thomas Fröhlich, Georg J. Arnold, Wolfgang Mikulits, Christine Haider, Angelika M. Vollmar,  and  Stefan Zahler
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=8342

MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1α regulation
L Liu, Y Wang, R Bai, K Yang and Z Tian
http://www.nature.com/oncsis/journal/v5/n5/abs/oncsis201635a.html

Short-term hypoxia synergizes with interleukin 15 priming in driving glycolytic gene transcription and supports human natural killer cell activities
Sonia Y. Velásquez, Doreen Killian, Jutta Schulte, Carsten Sticht, Manfred Thiel, and Holger A. Lindner
http://www.jbc.org/content/early/2016/04/28/jbc.M116.721753.abstract

Prognostic Significance of Carbonic Anhydrase IX Expression in Cancer Patients: A Meta-Analysis
Simon J. A. van Kuijk, Ala Yaromina, Ruud Houben, Raymon Niemans, Philippe Lambin, and Ludwig J. Dubois
http://journal.frontiersin.org/article/10.3389/fonc.2016.00069/full

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mTOR / AMPK
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Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor
Vanessa S. Rodrik-Outmezguine, Masanori Okaniwa, Zhan Yao, Chris J. Novotny, Claire McWhirter, Arpitha Banaji
Helen Won, Wai Wong, Mike Berger, Elisa de Stanchina, Derek G. Barratt, Sabina Cosulich, Teresa Klinowska, Neal Rosen, Kevan M. Shokat
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature17963.html

mTOR Inhibition Synergizes with Reduced IRES-mediated Translation of Cyclin D1 and c-MYC to Treat Glioblastoma
Brent Holmes, Jihye Lee, Kenna A. Landon, Angelica Benavides-Serrato, Tariq Bashir, Michael E. Jung, Alan Lichtenstein, and Joseph Gera
http://www.jbc.org/content/early/2016/05/11/jbc.M116.726927.abstract

The 4E-BP-eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes
Lomon So , Jongdae Lee, Miguel Palafox, Sharmila Mallya, Chaz G. Woxland, Meztli Arguello, Morgan L. Truitt, Nahum Sonenberg, Davide Ruggero, David A. Fruman
http://stke.sciencemag.org/content/9/430/ra57

Differential AMPK Recognition Mechanism of Ca2+/Calmodulin-dependent Protein Kinase Kinase Isoforms
Yuya Fujiwara, Yoshinori Kawaguchi, Tomohito Fujimoto, Naoki Kanayama, Masaki Magari, and Hiroshi Tokumitsu
http://www.jbc.org/content/early/2016/05/05/jbc.M116.727867.abstract

4EBP1/c-MYC/PUMA and NF-κB/EGR1/BIM pathways underlie cytotoxicity of mTOR dual inhibitors in malignant lymphoid cells
Seongseok Yun, Nicole D. Vincelette, Katherine L. B. Knorr, Luciana L. Almada, Paula A. Schneider, Kevin L. Peterson, Karen S. Flatten, Haiming Dai, Keith W. Pratz, Allan D. Hess, B. Douglas Smith, Judith E. Karp, Andrea E. Wahner Hendrickson, Martin E. Fernandez-Zapico, and Scott H. Kaufmann
http://bloodjournal.org/content/127/22/2711.abstract?etoc

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Miscellaneous
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Metabolite concentrations, fluxes and free energies imply efficient enzyme usage
Junyoung O Park, Sara A Rubin, Yi-Fan Xu, Daniel Amador-Noguez, Jing Fan, Tomer Shlomi & Joshua D Rabinowitz
Rabinowitz
http://www.nature.com/articles/nchembio.2077.epdf

Metabolic pathways regulated by TAp73 in response to oxidative stress
Massimiliano Agostini, Margherita Annicchiarico-Petruzzelli, Gerry Melino,  and  Alessandro Rufini
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=8935

Metabolomics and metabolic pathway networks from human colorectal cancers, adjacent mucosa, and stool
Brown  D, Rao  S, Weir  T, O’Malia  J, Bazan  M, Brown  R, Ryan  E
http://www.cancerandmetabolism.com/content/4/1/11/abstract

AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment
Natalie A. Daurio, Stephen W. Tuttle, Andrew J. Worth, Ethan Y. Song, Julianne M. Davis, Nathaniel W. Snyder, Ian A. Blair, and Constantinos Koumenis
http://cancerres.aacrjournals.org/content/76/11/3295.abstract?etoc

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Reviews
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Hallmarks of cancer stem cell metabolism
Patricia Sancho, David Barneda and Christopher Heeschen
http://www.nature.com/bjc/journal/vaop/ncurrent/full/bjc2016152a.html

Cancer metabolism: a therapeutic perspective
Ubaldo E. Martinez-Outschoorn, Maria Peiris-Pagés, Richard G. Pestell, Federica Sotgia & Michael P. Lisanti
http://www.nature.com/nrclinonc/journal/vaop/ncurrent/abs/nrclinonc.2016.60.html

Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer
Q Qu, F Zeng, X Liu, Q J Wang and F Deng
http://www.nature.com/cddis/journal/v7/n5/abs/cddis2016132a.html

TORC2 Structure and Function
Christl Gaubitz, Manoel Prouteau, Beata Kusmider, Robbie Loewith
http://www.cell.com/trends/biochemical-sciences/abstract/S0968-0004(16)30004-4

Special issue about mitochondrial Complex I in BBA – Bioenergetics
http://www.sciencedirect.com/science/journal/00052728/1857/7

Glutamine transport. From energy supply to sensing and beyond
Mariafrancesca Scalise, Lorena Pochini, Michele Galluccio, Cesare Indiveri
http://www.sciencedirect.com/science/article/pii/S0005272816300524

The ATPase Inhibitory Factor 1 (IF1): A master regulator of energy metabolism and of cell survival
Javier García-Bermúdez, José M. Cuezva
http://www.sciencedirect.com/science/article/pii/S0005272816300238

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Comments
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PGC1α drives a metabolic block on prostate cancer progression
Martina Wallace and Christian M. Metallo
http://www.nature.com/ncb/journal/v18/n6/full/ncb3365.html

You Are What You Eat: Linking Metabolic Asymmetry and Cell Fate Choice
Lisa Landskron, Juergen A. Knoblich
http://www.cell.com/developmental-cell/fulltext/S1534-5807(16)30237-4

Starving Intestinal Inflammation with the Amino Acid Sensor GCN2
Xavier S. Revelo, Shawn Winer, Daniel A. Winer
http://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30172-3

eIF4A moonlights as an off switch for TORC1
Marta M Swierczynska and Michael N Hall
http://EMBOJ.embopress.org/content/35/10/1013?etoc

Hydroxylation-independent HIF-1α stabilization through PKA: A new paradigm for hypoxia signaling
Eóin N. McNamee , Christine Vohwinkel, Holger K. Eltzschig
http://stke.sciencemag.org/content/9/430/fs11

4E-BP2 hardwires lymphocytes for rapamycin sensitivity
Robert T. Abraham
http://stke.sciencemag.org/content/9/430/fs10

Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine
Yangzom D. Bhutia, Ellappan Babu, and Vadivel Ganapathy
http://www.biochemj.org/content/473/11/1503?etoc

Collaborating tumor cells overcome multitargeted antiangiogenic therapies
http://stm.sciencemag.org/content/8/338/338ec77

mTORC1 Signaling Allows Cancer Cells to Escape Glycolytic Dependency
http://cancerdiscovery.aacrjournals.org/content/6/5/469.2.abstract?etoc

MYC-Overexpressing TNBCs Depend on Fatty Acid Oxidation
http://cancerdiscovery.aacrjournals.org/content/6/5/OF5.abstract?etoc

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