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Cancer & Metabolism

Luke W Thomas, Jenna M Stephen, Cinzia Esposito, Simon Hoer, Robin Antrobus, Afshan Ahmed, Hasan Al-Habib, Margaret Ashcroft
Background: Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus, mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is critical for regulating intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand...
2019: Cancer & Metabolism
Yongxian Zhuang, Reynold C Ly, Carleigh V Frazier, Jia Yu, Sisi Qin, Xiao-Yang Fan, Matthew P Goetz, Judy C Boughey, Richard Weinshilboum, Liewei Wang
Background: The role of tumor protein D54 in breast cancer has not been studied and its function in breast cancer remains unclear. In our previous pharmacogenomic studies using lymphoblastoid cell line (LCL), this protein has been identified to affect metformin response. Although metformin has been widely studied as a prophylactic and chemotherapeutic drug, there is still a lack of biomarkers predicting the response to metformin in breast cancer. In this study, we revealed the novel function of TPD54 in breast cancer through understanding how TPD54 altered the cancer cell sensitivity to metformin...
2019: Cancer & Metabolism
Xiangfeng Niu, Ying-Jr Chen, Peter A Crawford, Gary J Patti
Background: Recent in vitro and in vivo work has shown that lactate provides an important source of carbon for metabolic reactions in cancer cell mitochondria. An interesting question is whether lactate is oxidized by lactate dehydrogenase (LDH) in the cytosol and/or in mitochondria. Since metabolic processes in the cytosol and mitochondria are affected by redox balance, the location of LDH may have important regulatory implications in cancer metabolism. Methods: Within most mammalian cells, metabolic processes are physically separated by membrane-bound compartments...
2018: Cancer & Metabolism
Timothy J Humpton, Andreas K Hock, Oliver D K Maddocks, Karen H Vousden
Background: In response to oncogenic stress, the tumour suppressor protein p53 can induce the elimination of cells through induction of cell death or senescence, helping to restrain malignant progression. Conversely, under nutrient stress, p53 can protect cells by supporting metabolic adaptation. Many cancers express mutant p53 proteins that have lost the cell-elimination properties of wild-type p53. However, a previous report showed that a tumour-derived mutant can retain the ability to support cells under glutamine starvation...
2018: Cancer & Metabolism
Min Lu, Sydney M Sanderson, Amelia Zessin, Kathleen A Ashcraft, Lee W Jones, Mark W Dewhirst, Jason W Locasale, David S Hsu
Background: While self-reported exercise is associated with a reduction in the risk of recurrence in colorectal cancer, the molecular mechanisms underpinning this relationship are unknown. Furthermore, the effect of exercise on intratumoral metabolic processes has not been investigated in detail in human cancers. In our current study, we generated six colorectal patient patient-derived xenografts (CRC PDXs) models and treated each PDX to voluntary wheel running (exercise) for 6-8 weeks or no exposure to the wheel (control)...
2018: Cancer & Metabolism
Jonathan Tucci, Waseem Alhushki, Ting Chen, Xia Sheng, Yong-Mi Kim, Steven D Mittelman
Background: It is becoming increasingly recognized that weight and nutritional status can impact cancer survival. We have previously shown that obese mice with syngeneic acute lymphoblastic leukemia (ALL) have poorer response to chemotherapy treatment than control mice. We therefore investigated whether dietary intervention could improve outcome from the most common pediatric cancer, ALL. Methods: Diet-induced obese (DIO) mice raised on a 60% calories from fat diet and control mice were implanted with syngeneic ALL cells...
2018: Cancer & Metabolism
Alissandra L Hillis, Allison N Lau, Camille X Devoe, Talya L Dayton, Laura V Danai, Dolores Di Vizio, Matthew G Vander Heiden
Background: While most cancer cells preferentially express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), PKM2 is dispensable for tumor development in several mouse cancer models. PKM2 is expressed in human pancreatic cancer, and there have been conflicting reports on the association of PKM2 expression and pancreatic cancer patient survival, but whether PKM2 is required for pancreatic cancer progression is unknown. To investigate the role of PKM2 in pancreatic cancer, we used a conditional allele to delete PKM2 in a mouse model of pancreatic ductal adenocarcinoma (PDAC)...
2018: Cancer & Metabolism
Dipti Athavale, Surbhi Chouhan, Vimal Pandey, Shyamananda Singh Mayengbam, Snahlata Singh, Manoj Kumar Bhat
Background: PCSK9 regulates low-density lipoprotein cholesterol (LDLc) level and has been implicated in hypercholesterolemia. Aberrant plasma lipid profile is often associated with various cancers. Clinically, the relationship between altered serum lipid level and hepatocellular carcinoma (HCC) has been documented; however, the underlying cause and implications of such dyslipidemia remain unclear. Methods: The present study includes the use of HepG2 tumor xenograft model to study the potential role of glucose (by providing 15% glucose via drinking water) in regulating PCSK9 expression and associated hypercholesterolemia...
2018: Cancer & Metabolism
Costas Koufaris, Roland Nilsson
Background: The folate-coupled metabolic enzyme MTHFD2 is overexpressed in many tumor types and required for cancer cell proliferation, and is therefore of interest as a potential cancer therapeutic target. However, recent evidence suggests that MTHFD2 has a non-enzymatic function which may underlie the dependence of cancer cells on this protein. Understanding this non-enzymatic function is important for optimal targeting of MTHFD2 in cancer. Methods: To identify potential non-enzymatic functions of MTHFD2, we defined its interacting proteins using co-immunoprecipitation and mass spectrometry and integrated this information with large-scale co-expression analysis, protein dynamics, and gene expression response to MTHFD2 knockdown...
2018: Cancer & Metabolism
Jack Mottahedeh, Michael C Haffner, Tristan R Grogan, Takao Hashimoto, Preston D Crowell, Himisha Beltran, Andrea Sboner, Rohan Bareja, David Esopi, William B Isaacs, Srinivasan Yegnasubramanian, Matthew B Rettig, David A Elashoff, Elizabeth A Platz, Angelo M De Marzo, Michael A Teitell, Andrew S Goldstein
Background: Cancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD+ ) which is maintained by a balance of NAD+ hydrolase activity and NAD+ salvage activity. We recently reported that human prostate cancer can be initiated following oncogene expression in progenitor-like luminal cells marked by low expression of the NAD+ -consuming enzyme CD38. CD38 expression is reduced in prostate cancer compared to benign prostate, suggesting that tumor cells may reduce CD38 expression in order to enhance pools of NAD+ ...
2018: Cancer & Metabolism
Mohamed A Abu El Maaty, Yasamin Dabiri, Fadi Almouhanna, Biljana Blagojevic, Jannick Theobald, Michael Büttner, Stefan Wölfl
Background: We have previously identified 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ], the bioactive form of vitamin D3 , as a potent regulator of energy-utilization and nutrient-sensing pathways in prostate cancer cells. In the current study, we investigated the effects of 1,25(OH)2 D3 on breast cancer (BCa) cell metabolism using cell lines representing distinct molecular subtypes, luminal (MCF-7 and T-47D), and triple-negative BCa (MDA-MB-231, MDA-MB-468, and HCC-1143). Methods: 1,25(OH)2 D3 's effect on BCa cell metabolism was evaluated by employing a combination of real-time measurements of glycolysis/oxygen consumption rates using a biosensor chip system, GC/MS-based metabolomics, gene expression analysis, and assessment of overall energy levels...
2018: Cancer & Metabolism
Manan M Mehta, Samuel E Weinberg, Elizabeth M Steinert, Krishan Chhiba, Carlos Alberto Martinez, Peng Gao, Harris R Perlman, Paul Bryce, Nissim Hay, Navdeep S Chandel
Background: T cells and cancer cells utilize glycolysis for proliferation. The hexokinase (1-4) family of enzymes catalyze the first step of glycolysis. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. HK2 is required for the development and/or growth of cancer in several cancer models, but the necessity of HK2 in T cells is not fully understood. The clinical applicability of HK2 inhibition in cancer may be significantly limited by any potential negative effects of HK2 inhibition on T cells...
2018: Cancer & Metabolism
Ashley R Maiuri, Hongde Li, Barry D Stein, Jason M Tennessen, Heather M O'Hagan
Background: Inflammation, metabolism, and epigenetic modulation are highly interconnected processes that can be altered during tumorigenesis. However, because of the complexity of these interactions, direct cause and effect during tumorigenesis have been difficult to prove. Previously, using a murine model of inflammation-induced colon tumorigenesis, we determined that the promoter of the catalytic subunit of DNA polymerase gamma ( Polg ) is DNA hypermethylated and silenced in inflammation-induced tumors, but not in non-inflammation-induced (mock) tumors, suggesting that inflammation can induce silencing of Polg through promoting DNA methylation during tumorigenesis...
2018: Cancer & Metabolism
Shili Xu, Arthur Catapang, Daniel Braas, Linsey Stiles, Hanna M Doh, Jason T Lee, Thomas G Graeber, Robert Damoiseaux, Orian Shirihai, Harvey R Herschman
Background: Precision medicine therapies require identification of unique molecular cancer characteristics. Hexokinase (HK) activity has been proposed as a therapeutic target; however, different hexokinase isoforms have not been well characterized as alternative targets. While HK2 is highly expressed in the majority of cancers, cancer subtypes with differential HK1 and HK2 expression have not been characterized for their sensitivities to HK2 silencing. Methods: HK1 and HK2 expression in the Cancer Cell Line Encyclopedia dataset was analyzed...
2018: Cancer & Metabolism
Catharina Bartmann, Sudha R Janaki Raman, Jessica Flöter, Almut Schulze, Katrin Bahlke, Jana Willingstorfer, Maria Strunz, Achim Wöckel, Rainer J Klement, Michaela Kapp, Cholpon S Djuzenova, Christoph Otto, Ulrike Kämmerer
Background: Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2-6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro...
2018: Cancer & Metabolism
Talya L Dayton, Vasilena Gocheva, Kathryn M Miller, Arjun Bhutkar, Caroline A Lewis, Roderick T Bronson, Matthew G Vander Heiden, Tyler Jacks
Background: Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of the glycolytic enzyme pyruvate kinase. PKM2 expression is associated with embryogenesis, tissue regeneration, and cancer. PKM2 is also the pyruvate kinase isoform expressed in most wild-type adult tissues, with PKM1 restricted primarily to skeletal muscle, heart, and brain. To interrogate the functional requirement for PKM2 during tumor initiation in an autochthonous mouse model for soft tissue sarcoma (STS), we used a conditional Pkm2 allele ( Pkm2 fl ) to abolish PKM2 expression...
2018: Cancer & Metabolism
Matthew Garrett, Jantzen Sperry, Daniel Braas, Weihong Yan, Thuc M Le, Jack Mottahedeh, Kirsten Ludwig, Ascia Eskin, Yue Qin, Rachelle Levy, Joshua J Breunig, Frank Pajonk, Thomas G Graeber, Caius G Radu, Heather Christofk, Robert M Prins, Albert Lai, Linda M Liau, Giovanni Coppola, Harley I Kornblum
Background: There is considerable interest in defining the metabolic abnormalities of IDH mutant tumors to exploit for therapy. While most studies have attempted to discern function by using cell lines transduced with exogenous IDH mutant enzyme, in this study, we perform unbiased metabolomics to discover metabolic differences between a cohort of patient-derived IDH1 mutant and IDH wildtype gliomaspheres. Methods: Using both our own microarray and the TCGA datasets, we performed KEGG analysis to define pathways differentially enriched in IDH1 mutant and IDH wildtype cells and tumors...
2018: Cancer & Metabolism
Chen Dai, Jennifer Arceo, James Arnold, Arun Sreekumar, Norman J Dovichi, Jun Li, Laurie E Littlepage
Background: The complex yet interrelated connections between cancer metabolism and oncogenic driver genes are relatively unexplored but have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. The goal of this study was to identify global metabolic profiles of breast tumors isolated from multiple transgenic mouse models and to identify unique metabolic signatures driven by these oncogenes. Methods: Using mass spectrometry (GC-MS, LC-MS/MS, and capillary zone electrophoresis (CZE)-MS platforms), we quantified and compared the levels of 374 metabolites in breast tissue from normal and transgenic mouse breast cancer models overexpressing a panel of oncogenes (PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg)...
2018: Cancer & Metabolism
Pavithra Viswanath, Marina Radoul, Jose Luis Izquierdo-Garcia, Hema Artee Luchman, J Gregory Cairncross, Russell O Pieper, Joanna J Phillips, Sabrina M Ronen
Background: Magnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer. Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglutarate (2-HG) relative to wild-type IDH1 (IDHwt) gliomas. The goal of this study was to determine the molecular mechanism underlying this unusual metabolic reprogramming in IDHmut gliomas...
2018: Cancer & Metabolism
Parmanand Malvi, Balkrishna Chaube, Shivendra Vikram Singh, Naoshad Mohammad, Maleppillil Vavachan Vijayakumar, Snahlata Singh, Surbhi Chouhan, Manoj Kumar Bhat
Background: Obesity is associated with increased risk, poor prognosis and outcome of therapy, in various cancers. Obesity-associated factors or adipokines, especially leptin and resistin, are purported to promote growth, survival, proliferation, and invasiveness of cancer cells. However, the mechanistic link between these adipokines and therapeutic response in malignancies is not clearly understood. Methods: ob/ob and db/db mouse models were used in this study to evaluate the role of leptin and resistin towards the outcome of dacarbazine (DTIC) therapy in melanoma...
2018: Cancer & Metabolism
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