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Lactate AND MCT4

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https://www.readbyqxmd.com/read/29306548/disrupting-the-warburg-effect-re-routes-cancer-cells-to-oxphos-offering-a-vulnerability-point-via-ferroptosis-induced-cell-death
#1
REVIEW
Maša Ždralević, Milica Vučetić, Boutaina Daher, Ibtissam Marchiq, Scott K Parks, Jacques Pouysségur
The evolution of life from extreme hypoxic environments to an oxygen-rich atmosphere has progressively selected for successful metabolic, enzymatic and bioenergetic networks through which a myriad of organisms survive the most extreme environmental conditions. From the two lethal environments anoxia/high O2, cells have developed survival strategies through expression of the transcriptional factors ATF4, HIF1 and NRF2. Cancer cells largely exploit these factors to thrive and resist therapies. In this review, we report and discuss the potential therapeutic benefit of disrupting the major Myc/Hypoxia-induced metabolic pathway, also known as fermentative glycolysis or "Warburg effect", in aggressive cancer cell lines...
December 28, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/29249221/sex-hormones-regulate-rat-hepatic-monocarboxylate-transporter-expression-and-membrane-trafficking
#2
Jieyun Cao, Michael Ng, Melanie A Felmlee
PURPOSE: Monocarboxylate transporters (MCTs) are involved in the transport of monocarboxylates such as ketone bodies, lactate, and pharmaceutical agents. CD147 functions as an ancillary protein for MCT1 and MCT4 for plasma membrane trafficking. Sex differences in MCT1 and MCT4 have been observed in muscle and reproductive tissues; however, there is a paucity of information on MCT sex differences in tissues involved in drug disposition. The objective of the present study was to quantify hepatic MCT1, MCT4 and CD147 mRNA, total cellular and membrane protein expression in males, over the estrous cycle in females and in ovariectomized (OVX) females...
2017: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29248134/pilot-study-demonstrating-metabolic-and-anti-proliferative-effects-of-in-vivo-anti-oxidant-supplementation-with-n-acetylcysteine-in-breast-cancer
#3
Daniel Monti, Federica Sotgia, Diana Whitaker-Menezes, Madalina Tuluc, Ruth Birbe, Adam Berger, Melissa Lazar, Paolo Cotzia, Rossitza Draganova-Tacheva, Zhao Lin, Marina Domingo-Vidal, Andrew Newberg, Michael P Lisanti, Ubaldo Martinez-Outschoorn
BACKGROUND: High oxidative stress as defined by hydroxyl and peroxyl activity is often found in the stroma of human breast cancers. Oxidative stress induces stromal catabolism, which promotes cancer aggressiveness. Stromal cells exposed to oxidative stress release catabolites such as lactate, which are up-taken by cancer cells to support mitochondrial oxidative phosphorylation. The transfer of catabolites between stromal and cancer cells leads to metabolic heterogeneity between these cells and increased cancer cell proliferation and reduced apoptosis in preclinical models...
June 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/29248133/hodgkin-lymphoma-a-complex-metabolic-ecosystem-with-glycolytic-reprogramming-of-the-tumor-microenvironment
#4
Lekha Mikkilineni, Diana Whitaker-Menezes, Marina Domingo-Vidal, John Sprandio, Paola Avena, Paolo Cotzia, Alina Dulau-Florea, Jerald Gong, Guldeep Uppal, Tingting Zhan, Benjamin Leiby, Zhao Lin, Barbara Pro, Federica Sotgia, Michael P Lisanti, Ubaldo Martinez-Outschoorn
BACKGROUND: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells...
June 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/29248132/mitochondrial-and-glycolytic-metabolic-compartmentalization-in-diffuse-large-b-cell-lymphoma
#5
Mahasweta Gooptu, Diana Whitaker-Menezes, John Sprandio, Marina Domingo-Vidal, Zhao Lin, Guldeep Uppal, Jerald Gong, Roberto Fratamico, Benjamin Leiby, Alina Dulau-Florea, Jaime Caro, Ubaldo Martinez-Outschoorn
Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism...
June 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/29248131/metabolic-coupling-and-the-reverse-warburg-effect-in-cancer-implications-for-novel-biomarker-and-anticancer-agent-development
#6
REVIEW
Lindsay Wilde, Megan Roche, Marina Domingo-Vidal, Katherina Tanson, Nancy Philp, Joseph Curry, Ubaldo Martinez-Outschoorn
Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis, or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation. Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize oxidative phosphorylation. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells...
June 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/29170050/identification-of-a-pyruvate-to-lactate-signature-in-pancreatic-intraductal-papillary-mucinous-neoplasms
#7
Alan R Penheiter, Dinesh K Deelchand, Emily Kittelson, Sibel Erdogan Damgard, Stephen J Murphy, Daniel R O'Brien, William R Bamlet, Marie R Passow, Thomas C Smyrk, Fergus J Couch, George Vasmatzis, John D Port, Małgorzata Marjańska, Stephanie K Carlson
OBJECTIVE: We used transcriptomic profiling and immunohistochemistry (IHC) to search for a functional imaging strategy to resolve common problems with morphological imaging of cystic neoplasms and benign cystic lesions of the pancreas. METHODS: Resected pancreatic cancer (n = 21) and normal pancreas were laser-capture micro-dissected, and transcripts were quantified by RNAseq. Functional imaging targets were validated at the protein level by IHC on a pancreatic adenocarcinoma tissue microarray and a newly created tissue microarray of resected intraductal papillary mucinous neoplasms (IPMNs) and IPMN-associated adenocarcinomas...
November 14, 2017: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
https://www.readbyqxmd.com/read/29163155/intracellular-hyper-acidification-potentiated-by-hydrogen-sulfide-mediates-invasive-and-therapy-resistant-cancer-cell-death
#8
Zheng-Wei Lee, Xin-Yi Teo, Zhi J Song, Dawn S Nin, Wisna Novera, Bok A Choo, Brian W Dymock, Philip K Moore, Ruby Y-J Huang, Lih-Wen Deng
Slow and continuous release of H2S by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death. The present study investigated the potency of H2S released by GYY4137 against invasive and radio- as well as chemo-resistant cancers, known to be glycolytically active...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29050199/pre-clinical-pharmacology-of-azd3965-a-selective-inhibitor-of-mct1-dlbcl-nhl-and-burkitt-s-lymphoma-anti-tumor-activity
#9
Nicola J Curtis, Lorraine Mooney, Lorna Hopcroft, Filippos Michopoulos, Nichola Whalley, Haihong Zhong, Clare Murray, Armelle Logie, Mitchell Revill, Kate F Byth, Amanda D Benjamin, Mike A Firth, Stephen Green, Paul D Smith, Susan E Critchlow
Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29026134/mct1-and-mct4-expression-and-lactate-flux-activity-increase-during-white-and-brown-adipogenesis-and-impact-adipocyte-metabolism
#10
Charlotte Petersen, Mette D Nielsen, Elise S Andersen, Astrid L Basse, Marie S Isidor, Lasse K Markussen, Birgitte M Viuff, Ian H Lambert, Jacob B Hansen, Stine F Pedersen
Adipose tissue takes up glucose and releases lactate, thereby contributing significantly to systemic glucose and lactate homeostasis. This implies the necessity of upregulation of net acid and lactate flux capacity during adipocyte differentiation and function. However, the regulation of lactate- and acid/base transporters in adipocytes is poorly understood. Here, we tested the hypothesis that adipocyte thermogenesis, browning and differentiation are associated with an upregulation of plasma membrane lactate and acid/base transport capacity that in turn is important for adipocyte metabolism...
October 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28959247/microbiome-metabolome-responses-to-a-high-grain-diet-associated-with-the-hind-gut-health-of-goats
#11
Shiyu Tao, Ping Tian, Yanwen Luo, Jing Tian, Canfeng Hua, Yali Geng, Rihua Cong, Yingdong Ni, Ruqian Zhao
Studies on the effect of a high-concentrate (HC) diet on the hindgut microbiota and metabolome of ruminants are rarely reported. We used 454 pyrosequencing of 16S rDNA genes and gas chromatography-mass spectrometry to evaluate the effects of long-term feeding (HL) or short-term (HS) feeding of an HC diet on changes in bacterial microbiota and their metabolites in the hindgut, with Guanzhong goat as a ruminant model. Results indicated that an HC diet decreased bacterial diversity and induced metabolic disorder in the hindgut...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28923861/mct1-inhibitor-azd3965-increases-mitochondrial-metabolism-facilitating-combination-therapy-and-noninvasive-magnetic-resonance-spectroscopy
#12
Mounia Beloueche-Babari, Slawomir Wantuch, Teresa Casals Galobart, Markella Koniordou, Harold G Parkes, Vaitha Arunan, Yuen-Li Chung, Thomas R Eykyn, Paul D Smith, Martin O Leach
Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux...
November 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28866133/mda-mb-231-breast-cancer-cells-fuel-osteoclast-metabolism-and-activity-a-new-rationale-for-the-pathogenesis-of-osteolytic-bone-metastases
#13
Silvia Lemma, Gemma Di Pompo, Paolo E Porporato, Martina Sboarina, Shonagh Russell, Robert J Gillies, Nicola Baldini, Pierre Sonveaux, Sofia Avnet
Recent progress in dissecting the molecular paracrine circuits of cancer and stromal cells in bone metastases (BM) are offering new options to improve current merely palliative approach. The study of tumor-stroma metabolic interplay may further ameliorate this scenario. In this context, we demonstrated that highly glycolytic MDA-MB-231 cancer cells, that form osteolytic BM in vivo, release a large amount of lactate at a significantly higher level than MCF7 cells. Thus, we speculated that lactate released from carcinoma cells is uptaken and metabolically used by osteoclasts, the key players of osteolysis associated with BM...
September 1, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28865453/arginine-vasopressin-altered-the-expression-of-monocarboxylate-transporters-in-cultured-astrocytes-isolated-from-stroke-prone-spontaneously-hypertensive-rats-and-congenic-shrpch1_18-rats
#14
Kazuo Yamagata, Natsumi Takahashi, Nozomi Akita, Toru Nabika
BACKGROUND: Astrocytes support a range of brain functions as well as neuronal survival, but their detailed relationship with stroke-related edema is not well understood. We previously demonstrated that the release of lactate from astrocytes isolated from stroke-prone spontaneously hypertensive rats (SHRSP/Izm) was attenuated under stroke conditions. The supply of lactate to neurons is regulated by astrocytic monocarboxylate transporters (MCTs). The purpose of this study was to examine the contributions of arginine vasopressin (AVP) and/or hypoxia and reoxygenation (H/R) to the regulation of MCTs and neurotrophic factor in astrocytes obtained from SHRSP/Izm and congenic SHRpch1_18 rats...
September 2, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28846107/nuclear-factor-e2-related-factor-2-has-a-differential-impact-on-mct1-and-mct4-lactate-carrier-expression-in-colonic-epithelial-cells-a-condition-favoring-metabolic-symbiosis-between-colorectal-cancer-and-stromal-cells
#15
K Diehl, L-A Dinges, O Helm, N Ammar, D Plundrich, A Arlt, C Röcken, S Sebens, H Schäfer
Malignant tumors, such as colorectal cancer (CRC), are heterogeneous diseases characterized by distinct metabolic phenotypes. These include Warburg- and reverse Warburg phenotypes depending on differential distribution of the lactate carrier proteins monocarboxylate transporter-4 and -1 (MCT4 and MCT1). Here, we elucidated the role of the antioxidant transcription factor nuclear factor E2-related factor-2 (Nrf2) as the key regulator of cellular adaptation to inflammatory/environmental stress in shaping the metabolism toward a reverse Warburg phenotype in malignant and premalignant colonic epithelial cells...
August 28, 2017: Oncogene
https://www.readbyqxmd.com/read/28741686/gpr55-receptor-antagonist-decreases-glycolytic-activity-in-panc-1-pancreatic-cancer-cell-line-and-tumor-xenografts
#16
Michel Bernier, Jonathan Catazaro, Nagendra S Singh, Artur Wnorowski, Anna Boguszewska-Czubara, Krzysztof Jozwiak, Robert Powers, Irving W Wainer
The Warburg effect is a predominant metabolic pathway in cancer cells characterized by enhanced glucose uptake and its conversion to l-lactate and is associated with upregulated expression of HIF-1α and activation of the EGFR-MEK-ERK, Wnt-β-catenin, and PI3K-AKT signaling pathways. (R,R')-4'-methoxy-1-naphthylfenoterol ((R,R')-MNF) significantly reduces proliferation, survival, and motility of PANC-1 pancreatic cancer cells through inhibition of the GPR55 receptor. We examined (R,R')-MNF's effect on glycolysis in PANC-1 cells and tumors...
November 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28599272/pre-clinical-pharmacology-of-azd3965-a-selective-inhibitor-of-mct1-dlbcl-nhl-and-burkitt-s-lymphoma-anti-tumor-activity
#17
Nicola J Curtis, Lorraine Mooney, Lorna Hopcroft, Filippos Michopoulos, Nichola Whalley, Haihong Zhong, Clare Murray, Armelle Logie, Mitchell Revill, Kate F Byth, Amanda D Benjamin, Mike A Firth, Stephen Green, Paul D Smith, Susan E Critchlow
Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28471448/mir-1-suppresses-tumor-cell-proliferation-in-colorectal-cancer-by-inhibition-of-smad3-mediated-tumor-glycolysis
#18
Wanfu Xu, Zijing Zhang, Kejian Zou, Yang Cheng, Min Yang, Huan Chen, Hongli Wang, Junhong Zhao, Peiyu Chen, Liying He, Xinwen Chen, Lanlan Geng, Sitang Gong
Aberrant expression of microRNA (miR)-1 has been observed in many human malignancies. However, the function and underlying mechanism of miR-1 remains elusive. To address the specific role of miR-1 in tumor glycolysis using the gain- or loss-of-function studies. Metabolic studies combined with gene expression analysis were performed in vitro and in vivo. We demonstrated aberrant expression of miR-1 in aerobic glycolysis, the Warburg effect, in cancer cells. MiR-1 suppressed aerobic glycolysis and tumor cell proliferation via inactivation of Smad3 and targeting HIF-1α, leading to reduce HK2 and MCT4 expression, which illustrated a novel pathway to mediate aerobic glycolysis in cancer cells...
May 4, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28440446/temporal-and-spatial-changes-of-monocarboxylate-transporter-4-expression-in-the-hippocampal-ca1-region-following-transient-forebrain-ischemia-in-the-mongolian-gerbil
#19
Dae Young Yoo, Joon Ha Park, Kwon Young Lee, Hyun Jung Kwon, Hyo Young Jung, Jong Whi Kim, Dae Won Kim, Jung Hoon Choi, Seung Myung Moon, Yeo Sung Yoon, Moo-Ho Won, In Koo Hwang
Transient forebrain ischemia depletes glucose and oxygen levels in the brain. In this pathological condition, lactate serves an important role in cellular metabolism as the end product of glycolysis. The present study investigated the expression of monocarboxylate transporter 4 (MCT4) in lactate metabolism in the hippocampal CA1 region following induction of transient forebrain ischemia. MCT4 immunoreactivity was detected in CA1 pyramidal cells of the sham-operated group. Animals from the ischemic group exhibited a transient decrease in MCT4 immunoreactivity in the CA1 region between 30 min and 3 h following ischemia compared with the sham‑operated group...
June 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28428273/assessing-prostate-cancer-aggressiveness-with-hyperpolarized-dual-agent-3d-dynamic-imaging-of-metabolism-and-perfusion
#20
Hsin-Yu Chen, Peder E Z Larson, Robert A Bok, Cornelius von Morze, Renuka Sriram, Romelyn Delos Santos, Justin Delos Santos, Jeremy W Gordon, Naeim Bahrami, Marcus Ferrone, John Kurhanewicz, Daniel B Vigneron
New magnetic resonance (MR) molecular imaging techniques offer the potential for noninvasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a three-dimensional dynamic dual-agent hyperpolarized (13)C magnetic resonance spectroscopic imaging approach with (13)C-pyruvate and (13)C-urea to investigate differences in perfusion and metabolism between low- and high-grade tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer...
June 15, 2017: Cancer Research
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