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Lactate AND MCT4

Qionglin Zhou, Jin Xu, Meiqing Liu, Lu He, Kai Zhang, Yiyuan Yang, Xiao Yang, Hong Zhou, Mingzhu Tang, Liqun Lu, Zhe Chen, Linxi Chen, Lanfang Li
Apelin is the endogenous ligand for the G protein-coupled receptor APJ. Both apelin and APJ receptor are distributed in vascular smooth muscle cells (VSMCs) and play important roles in the cardiovascular system. Our previous reports have indicated that apelin-13 promoted the proliferation of VSMCs, but its exact mechanism remains to be further explored. The results of the present study demonstrated that the Warburg effect plays a pivotal role in apelin-13-induced human aortic vascular smooth muscle cells (HA-VSMCs) proliferation...
January 31, 2019: Journal of Cellular Physiology
Jun Yu, Jiantao Sun, Yongsheng Fan, Jianmei Su, Jie Xie, Yu Wu, Xi Liu, Chunhong Wang
Sertoli cells (SCs) provide lactate as an energy substrate to develop germ cells during spermatogenesis. Lead (Pb) and cadmium (Cd) can induce SC toxicity. However, the mechanisms remain unclear. This study aimed to investigate the molecular mechanisms by which Pb and Cd alter lactate transport and production by SCs. Mouse SC line (15P-1 cells) were cultured in the absence and presence of lead acetate (PbAc, 1, 10, 20 and 30 μM) or cadmium chloride (CdCl2 , 0.5, 5, 10 and 15 μM) for 24 h. The results showed that PbAc exposure significantly decreased lactate dehydrogenase (LDH) activity and mRNA level, intracellular and extracellular lactate, and MCT4 and CD147 protein levels but increased MCT4 and CD147 mRNA levels...
January 4, 2019: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Alin Rai, David W Greening, Maoshan Chen, Rong Xu, Hong Ji, Richard J Simpson
Cancer-associated fibroblasts (CAFs) are a heterogeneous population of activated fibroblasts that constitute a dominant cellular component of the tumour microenvironment (TME) performing distinct functions. Here, we investigated the role of tumour-derived exosomes in activating quiescent fibroblasts into distinct functional subtypes. Proteomic profiling and functional dissection revealed that early (SW480) and late-stage (SW620) colorectal cancer (CRC) cell-derived exosomes both activated normal quiescent fibroblasts (α-SMA- , CAV+ , FAP+ , VIM+ ) into CAF-like fibroblasts (α-SMA+ , CAV- FAP+ , VIM+ )...
December 23, 2018: Proteomics
Marina Radoul, Chloé Najac, Pavithra Viswanath, Joydeep Mukherjee, Mark Kelly, Anne Marie Gillespie, Myriam M Chaumeil, Pia Eriksson, Romelyn Delos Santos, Russell O Pieper, Sabrina M Ronen
Vorinostat is a histone deacetylase (HDAC) inhibitor that inhibits cell proliferation and induces apoptosis in solid tumors, and is in clinical trials for the treatment of glioblastoma (GBM). The goal of this study was to assess whether hyperpolarized 13 C MRS and magnetic resonance spectroscopic imaging (MRSI) can detect HDAC inhibition in GBM models. First, we confirmed HDAC inhibition in U87 GBM cells and evaluated real-time dynamic metabolic changes using a bioreactor system with live vorinostat-treated or control cells...
December 18, 2018: NMR in Biomedicine
Don Benjamin, Dimitri Robay, Sravanth K Hindupur, Jens Pohlmann, Marco Colombi, Mahmoud Y El-Shemerly, Sauveur-Michel Maira, Christoph Moroni, Heidi A Lane, Michael N Hall
Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H+ via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H+ efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase...
December 11, 2018: Cell Reports
Barrett L Updegraff, Xiaorong Zhou, Yabin Guo, Mahesh S Padanad, Pei-Hsuan Chen, Chendong Yang, Jessica Sudderth, Carla Rodriguez-Tirado, Luc Girard, John D Minna, Prashant Mishra, Ralph J DeBerardinis, Kathryn A O'Donnell
Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression...
November 20, 2018: Cell Reports
Linda S Forero-Quintero, Samantha Ames, Hans-Peter Schneider, Anne Thyssen, Christopher D Boone, Jacob T Andring, Robert McKenna, Joseph R Casey, Joachim W Deitmer, Holger M Becker
Monocarboxylate transporters (MCTs) mediate the proton-coupled exchange of high-energy metabolites, including lactate and pyruvate, between cells and tissues. The transport activity of MCT1, MCT2, and MCT4 can be facilitated by the extracellular carbonic anhydrase IV (CAIV) via a non-catalytic mechanism. Combining physiological measurements in HEK-293 cells and Xenopus oocytes with pulldown experiments, we analyzed the direct interaction between CAIV and the two MCT chaperones basigin (CD147) and embigin (GP70)...
November 16, 2018: Journal of Biological Chemistry
Simon J Park, Chase P Smith, Ryan R Wilbur, Charles P Cain, Sankeerth R Kallu, Srijan Valasapalli, Arpit Sahoo, Maheedhara R Guda, Andrew J Tsung, Kiran K Velpula
Monocarboxylate transporters (MCTs) represent a diverse group of transmembrane proteins encoded by the SLC16 gene family found ubiquitously across mammalian species. Two members of this family, MCT1 and MCT4, have been linked to key roles in the metabolic activity of tissues through the proton-coupled transport of monocarboxylates, most notably L-lactate, ketone bodies, and pyruvate. This review aims to provide an overview of MCT1 and MCT4, followed by the implications of their expression in a multitude of cancers and in glioblastoma (GBM) specifically...
2018: American Journal of Cancer Research
Xiaowen Guan, Mark A Bryniarski, Marilyn E Morris
Monocarboxylate transporter 1 (MCT1), also known as a L-lactate transporter, is a potential therapeutic target in cancer. The objectives of this study were to evaluate efficacy and assess concentration-effect relationships of AR-C155858 (a selective and potent MCT1 inhibitor) in murine 4T1 breast cancer cells and in the 4T1 tumor xenograft model. Western blotting of 4T1 cells demonstrated triple negative breast cancer (TNBC) characteristics and overexpression of MCT1 and CD147 (a MCT1 accessory protein), but absence of MCT4 expression...
November 5, 2018: AAPS Journal
Mao Zhang, Xiaofang Cheng, Ruozhi Dang, Weiwei Zhang, Jie Zhang, Zhongxiang Yao
Cerebral energy metabolism in Alzheimer disease (AD) has recently been given increasing attention. This study focuses on the alterations of cerebral lactate metabolism in the double-transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD. Immunofluorescence staining and Western blotting analysis were used to identify the alterations of lactate content and lactate transporters (MCT1, MCT2, MCT4) in APP/PS1 mouse brains, which display amyloid beta plaques, reduced amounts of neurons and oligodendrocytes, and increased quantity of astrocytes...
December 1, 2018: Journal of Neuropathology and Experimental Neurology
Kazuaki Hasegawa, Tatsuo Okui, Tsuyoshi Shimo, Soichiro Ibaragi, Hotaka Kawai, Shoji Ryumon, Koji Kishimoto, Yuka Okusha, Nur Mohammad Monsur Hassan, Akira Sasaki
Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically, as it can invade facial bones and cause bone pain that is undertreated and poorly understood. Here we studied HNSCC bone pain (HNSCC-BP) in an intratibial mouse xenograft model that uses a human HNSCC cell line (SAS cells). These mice develop HNSCC-BP associated with an upregulation of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in the dorsal root ganglia (DRGs) of sensory nerve cell bodies...
October 25, 2018: International Journal of Molecular Sciences
Yukio Abe, Yoshifumi Nakayama, Takefumi Katsuki, Yuzuru Inoue, Noritaka Minagawa, Takayuki Torigoe, Aiichiro Higure, Tatsuhiko Sako, Naoki Nagata, Keiji Hirata
AIM: Monocarboxylate transporter 4 (MCT4) is a proton pump that exchanges lactate through the plasma membrane. The present study investigated the clinical significance of the expression of MCT4 in patients with right- or left-sided colorectal cancer (CRC). METHODS: Surgical specimens from 237 CRC patients were immunohistochemically stained with polyclonal anti-MCT4 antibodies. The relationships among the MCT4 expression, the clinicopathological factors, and the prognosis were evaluated...
September 30, 2018: Asia-Pacific Journal of Clinical Oncology
Tilman Todenhöfer, Roland Seiler, Craig Stewart, Igor Moskalev, Jian Gao, Simroop Ladhar, Alireza Kamyabi, Nader Al Nakouzi, Tetsutaro Hayashi, Stephen Choi, Yuzhuo Wang, Sebastian Frees, Mads Daugaard, Htoo Zarni Oo, Pascale Fisel, Matthias Schwab, Elke Schaeffeler, James Douglas, Jörg Hennenlotter, Jens Bedke, Ewan A Gibb, Ladan Fazli, Arnulf Stenzl, Peter C Black
INTRODUCTION & OBJECTIVES: The significance of lactate transporters has been recognized in various cancer types, but their role in urothelial carcinoma (UC) remains mostly unknown. The aim of the present study was to investigate the functional importance of the monocarboxylate transporter (MCT) 4 in preclinical models of UC and to assess its relevance in patient tumors. MATERIALS & METHODS: The association of MCT4 expression with molecular subtypes and outcome was determined in The Cancer Genome Atlas (TCGA) cohort and two independent cohorts of patients with UC...
September 27, 2018: Molecular Cancer Therapeutics
Sara Bisetto, Diana Whitaker-Menezes, Nicole A Wilski, Madalina Tuluc, Joseph Curry, Tingting Zhan, Christopher M Snyder, Ubaldo E Martinez-Outschoorn, Nancy J Philp
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common human cancer and affects approximately 50,000 new patients every year in the US. The major risk factors for HNSCC are tobacco and alcohol consumption as well as oncogenic HPV infections. Despite advances in therapy, the overall survival rate for all-comers is only 50%. Understanding the biology of HNSCC is crucial to identifying new biomarkers, implementing early diagnostic approaches and developing novel therapies. As in several other cancers, HNSCC expresses elevated levels of MCT4, a member of the SLC16 family of monocarboxylate transporters...
2018: Frontiers in Oncology
Wanfu Xu, Fangyin Zeng, Songyu Li, Guihuan Li, Xiaoju Lai, Qiming Jane Wang, Fan Deng
Protein kinase C ε (PKCε) has emerged as an oncogenic protein kinase and plays important roles in cancer cell survival, proliferation, and invasion. It is, however, still unknown whether PKCε affects cell proliferation via glucose metabolism in cancer cells. Here we report a novel function of PKCε that provides growth advantages for cancer cells by enhancing tumor cells glycolysis. We found that either PKCε or Smad2/3 promoted aerobic glycolysis, expression of the glycolytic genes encoding HIF-1α, HKII, PFKP and MCT4, and tumor cell proliferation, while overexpression of PKCε or Smad3 enhanced aerobic glycolysis and cell proliferation in a protein kinase D- or TGF-β-independent manner in PC-3M and DU145 prostate cancer cells...
September 12, 2018: Cellular and Molecular Life Sciences: CMLS
Renuka Sriram, Jeremy Gordon, Celine Baligand, Fayyaz Ahamed, Justin Delos Santos, Hecong Qin, Robert A Bok, Daniel B Vigneron, John Kurhanewicz, Peder E Z Larson, Zhen J Wang
Optimal treatment selection for localized renal tumors is challenging due to their variable biological behavior and limited ability to pre-operatively assess their aggressiveness. We investigated hyperpolarized (HP) 13 C pyruvate MRI to noninvasively assess tumor lactate production and compartmentalization, which are strongly associated with renal tumor aggressiveness. Orthotopic tumors were created in mice using human renal cell carcinoma (RCC) lines (A498, 786-O, UOK262) with varying expression of lactate dehydrogenase A ( LDHA ) which catalyzes the pyruvate-to-lactate conversion, and varying expression of monocarboxylate transporter 4 ( MCT4 ) which mediates lactate export out of the cells...
September 5, 2018: Cancers
Yuki Kimura, Masaki Kobayashi, Masaru Asari, Issei Higuchi, Katsuya Narumi, Ayako Furugen, Ken Iseki
MCT1 (SLC16A1), MCT4 (SLC16A3), and MCT11 (SLC16A11) are members of the monocarboxylate transporter (MCT) family. MCT1 and MCT4 transport pH-related monocarboxylates, such as lactate and pyruvate. MCT11 may also be a proton-coupled monocarboxylate transporter. Although alterations of these substrates are involved in the pathology of cancer and diabetes, little is known about MCT polymorphisms. In this study, genetic variation was evaluated in SLC16A1, SLC16A3, and SLC16A11 in the Japanese population (healthy volunteers, n = 92)...
October 2018: Drug Metabolism and Pharmacokinetics
Maria Quanz, Eckhard Bender, Charlotte Kopitz, Sylvia Grünewald, Andreas Schlicker, Wolfgang Schwede, Ashley Eheim, Luisella Toschi, Roland Neuhaus, Carmen Richter, Joern Toedling, Claudia Merz, Ralf Lesche, Atanas Kamburov, Holger Siebeneicher, Marcus Bauser, Andrea Hägebarth
The lactate transporter SLC16A1 /monocarboxylate transporter 1 (MCT1) plays a central role in tumor cell energy homeostasis. In a cell-based screen, we identified a novel class of MCT1 inhibitors, including BAY-8002, which potently suppress bidirectional lactate transport. We investigated the antiproliferative activity of BAY-8002 in a panel of 246 cancer cell lines and show that hematopoietic tumor cells, in particular diffuse large B-cell lymphoma cell lines, and subsets of solid tumor models are particularly sensitive to MCT1 inhibition...
November 2018: Molecular Cancer Therapeutics
Yaping Long, Zihe Gao, Xiao Hu, Feng Xiang, Zhaozhen Wu, Jiahui Zhang, Xiao Han, Liyong Yin, Junfang Qin, Lan Lan, Fuzai Yin, Yue Wang
Monocarboxylate transporter-4 (MCT4), a monocarboxylic acid transporter, demonstrates significantly increased expression in the majority of malignancies. We performed an experiment using BALB/C mice, and our results showed that ShMCT4 transfection or the pharmaceutic inhibition of MCT4 with 7acc1 strengthens the activity of NK cells. The results of a calcein assay revealed that the cytotoxicity of NK cells was strengthened via inhibition of MCT4. In addition, ELISA testing showed that the content of perforin and CD107a was increased, and PCR amplification and immunoblotting revealed that the expression of NKG2D and H60 was upregulated after the inhibition of MCT4...
September 2018: Cancer Medicine
Jenny Lund, Vigdis Aas, Ragna H Tingstad, Alfons Van Hees, Nataša Nikolić
Once assumed only to be a waste product of anaerobe glycolytic activity, lactate is now recognized as an energy source in skeletal muscles. While lactate metabolism has been extensively studied in vivo, underlying cellular processes are poorly described. This study aimed to examine lactate metabolism in cultured human myotubes and to investigate effects of lactate exposure on metabolism of oleic acid and glucose. Lactic acid, fatty acid and glucose metabolism were studied in myotubes using [14 C(U)]lactic acid, [14 C]oleic acid and [14 C(U)]glucose, respectively...
June 29, 2018: Scientific Reports
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