The Experts below are selected from a list of 1629 Experts worldwide ranked by ideXlab platform
Judith D. Ochrietor - One of the best experts on this subject based on the ideXlab platform.
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The Basigin-variant-2 binding domain in the Ig0 domain of Basigin-variant-1 stimulates an immune response in the mouse monocyte RAW 264.7 cell line
The FASEB Journal, 2019Co-Authors: Abigail Delanie Tompa, Judith D. OchrietorAbstract:There are two main protein products of the Basigin gene. One protein, known as Basigin-variant-1 is expressed in the neural retina, specifically by the photoreceptor neurons. The other protein, known as Basigin-variant-2 is expressed throughout the body, including monocytes, as well as Muller glial cells and the retinal pigmented epithelium of the eye. A study by this laboratory indicates that the two Basigin gene products interact via their extracellular domains. A different study by another research group indicates that the Ig0 domain of Basigin-variant-1 can elicit an immune response in several cell lines. The purpose of the present study was to determine if the region of the Ig0 domain of Basigin-variant-1 thought to interact with Basigin-variant-2 is the same region that elicits an immune response. Recombinant versions of the Basigin-variant-1 Ig0 domain were incubated with mouse monocytic RAW 264.7 cells. After 24 hours, the cell culture medium was collected and assayed for the expression of the pro...
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Characterization of the Expression of Basigin Gene Products Within the Pineal Gland of Mice.
Cellular and molecular neurobiology, 2016Co-Authors: Derek Tokar, Paul J Linser, Leslie Van Ekeris, Judith D. OchrietorAbstract:The expression of Basigin gene products and monocarboxylate transporter-1 (MCT1) has been investigated within the mammalian neural retina and suggests a role for these proteins in cellular metabolism within that tissue. The purpose of the present study was to investigate the expression of these same proteins in the pineal gland of the mouse brain. Mouse pineal gland and neural retina RNA and protein were subjected to quantitative reverse transcription-polymerase chain reaction and immunoblotting analyses. In addition, paraffin-embedded sections of each tissue were analyzed for expression of Basigin gene products and MCT1 via immunohistochemistry. The results indicate that MCT1 and Basigin variant-2, but not Basigin variant-1, are expressed within the mouse pineal gland. The expression of Basigin variant-2 and MCT1 was localized to the capsule surrounding the gland. The position and relative amounts of the gene products suggest that they play a much less prominent role within the pineal gland than in the neural retina.
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Characterization of the Immunological Properties of Retina-Specific Basigin Variant-1
The FASEB Journal, 2015Co-Authors: Judith D. Ochrietor, Kyle Russell, Kyle McbrideAbstract:A recent study indicated that Basigin variant-1 can induce the expression of interleukin (IL)-6 in the U937 monocytic cell line via its amino-terminal immunoglobulin (Ig) domain. Basigin variant-1 ...
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Deletion of the Basigin gene results in reduced mitochondria in the neural retina.
Biochemical and biophysical research communications, 2013Co-Authors: Kristine Anne V. Pablo, Judith D. OchrietorAbstract:Basigin-null mice are characterized as blind from the time of eye opening, with degeneration of the retina beginning at 8weeks of age, and progressing until the entire photoreceptor cell layer is destroyed. It is likely that a metabolic deficiency underlies the blindness and degeneration phenotypes, as it has been determined that Basigin-null mice do not express the transporter protein monocarboxylate transporter one on the membrane of photoreceptor cells and inner segments, nor Muller cells of the neural retina, as is observed in normal mice. The purpose of the present study was to assess the health of mitochondria in normal and Basigin-null mice, specifically to determine if mitochondria within the Basigin-null mouse neural retina are metabolically active. This was achieved via a measurement of cytochrome C concentration and the expression of autophagy-specific proteins via ELISA analyses. Additionally, Mitotracker dyes were used to assess the number and relative activity of mitochondria. It was determined that cytochrome C concentrations and expression of autophagy-specific proteins were not increased in Basigin-null animals, as compared to control animals. Also, while Basigin-null mice do have metabolically active mitochondria, the amount of mitochondria was greatly reduced, when compared to control animals. The results suggest that a reduction in mitochondria is a result, rather than the cause, of the metabolic deficiency observed in Basigin-null mice, and likely occurs because of reduced metabolic activity in the absence of MCT1 expression.
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Characterization of Monocarboxylate Transporter 1 (MCT1) Binding Affinity for Basigin Gene Products and L1cam
Cellular and Molecular Neurobiology, 2010Co-Authors: John Howard, Nicole A. Finch, Judith D. OchrietorAbstract:The purpose of this study was to determine the binding affinities of Basigin gene products and neural cell adhesion molecule L1cam for monocarboxylate transporter-1 (MCT1). ELISA binding assays were performed in which recombinant proteins of the transmembrane domains of Basigin gene products and L1cam were incubated with MCT1 captured from mouse brain. It was determined that Basigin gene products bind MCT1 with moderate affinity, but L1cam does not bind MCT1. Despite a high degree of sequence conservation between Basigin gene products and L1cam, the sequences are different enough to prevent L1cam from interacting with MCT1.
Takashi Muramatsu - One of the best experts on this subject based on the ideXlab platform.
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Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners
Journal of biochemistry, 2015Co-Authors: Takashi MuramatsuAbstract:Basigin, also called CD147 or EMMPRIN, is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily. Basigin has isoforms; the common form (Basigin or Basigin-2) has two immunoglobulin domains, and the extended form (Basigin-1) has three. Basigin is the receptor for cyclophilins, S100A9 and platelet glycoprotein VI, whereas Basigin-1 serves as the receptor for the rod-derived cone viability factor. Basigin tightly associates with monocarboxylate transporters and is essential for their cell surface translocation and activities. In the same membrane plane, Basigin also associates with other proteins including GLUT1, CD44 and CD98. The carbohydrate portion of Basigin is recognized by lectins, such as galectin-3 and E-selectin. These molecular recognitions form the basis for the role of Basigin in the transport of nutrients, migration of inflammatory leukocytes and induction of matrix metalloproteinases. Basigin is important in vision, spermatogenesis and other physiological phenomena, and plays significant roles in the pathogenesis of numerous diseases, including cancer. Basigin is also the receptor for an invasive protein RH5, which is present in malaria parasites.
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Basigin: a multifunctional membrane protein with an emerging role in infections by malaria parasites.
Expert opinion on therapeutic targets, 2012Co-Authors: Takashi MuramatsuAbstract:Introduction: Malaria is one of the most serious infectious diseases at the beginning of the twenty-first century. Various membrane proteins are present in Plasmodium falciparum, the principal malaria pathogen. Among them, P. falciparum reticulocyte-binding protein homolog 5 (PfRh5) is indispensable for erythrocyte invasion, and has become a promising vaccine target. Basigin (CD147, EMMPRIN) has been identified as the erythrocyte receptor of PfRh5, and shown to be essential for the invasion of multiple strains of the pathogen. Areas covered: Fundamental information on Basigin is fully described, including structure as a member of the immunoglobulin superfamily and function based on its interactions with external molecules and with proteins within the same membrane. The involvement of Basigin in many diseases such as cancer and inflammatory diseases is also described, the implication being that anti-Basigin therapy might be helpful to treat certain illnesses. Finally, PfRh5 as a vaccine candidate is covere...
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Basigin expression and regulation in mouse ovary during the sexual maturation and development of corpus luteum.
Molecular reproduction and development, 2004Co-Authors: Hong Chang, Kenji Kadomatsu, Takashi Muramatsu, Zeng-ming YangAbstract:Basigin is a highly glycosylated transmembrane protein belonging to the immunoglobulin superfamily. Basigin-deficient male mice are azoospermic. The majority of Basigin null embryos die around the time of implantation. However, Basigin expression and regulation in mouse ovary is still unknown. The aim of this study was to investigate Basigin expression in mouse ovary during sexual maturation, gonadotropin treatment, and luteal development by in situ hybridization and immunohistochemistry. Both Basigin mRNA and immunostaining were not detected in the granulosa cells of preantral follicles until day 20 after birth. On day 30 after birth, Basigin immunostaining dropped to a basal level, while Basigin mRNA was still at a high level. Basigin expression was strongly induced by equine chorionic gonadotropin (eCG) treatment at 4 and 8 hr post-eCG injection. Both Basigin immunostaining and mRNA signals were strongly observed in the corpus luteum on days 2 and 3 post-hCG injection. However, no Basigin expression was detected from days 6 to 15 post-hCG injection. In conclusion, our data suggest that Basigin may play a role during the mouse follicle development and corpus luteum formation.
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retina specific expression of 5a11 Basigin 2 a member of the immunoglobulin gene superfamily
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Judith D. Ochrietor, Takashi Muramatsu, Tatiana P Moroz, Leslie Van Ekeris, Michael F Clamp, Stephanie C Jefferson, Ana C Decarvalho, James M Fadool, Graeme Wistow, Paul J LinserAbstract:PURPOSE 5A11/Basigin has recently been identified as a critical glycoprotein for full maturity and function of the mouse retina. However, the biological function of 5A11/Basigin has yet to be determined. Previous reports indicate the presence of multiple 5A11/Basigin polypeptides within the retina. Therefore, in an effort to determine the function of 5A11/Basigin, the molecular diversity of its expression was evaluated. METHODS Northern blot and immunoblot techniques were used to evaluate the number of forms of 5A11/Basigin in the mouse retina. cDNA cloning, using a mouse retina library or RT-PCR from rat, chicken, zebrafish, and human retina, was performed to determine the sequence of 5A11/Basigin transcripts. A peptide was generated, based on the deduced amino acid sequence, for subsequent antibody production. Localization of 5A11/Basigin expression was evaluated by immunoblot, immunohistochemistry, and real-time RT-PCR. RESULTS Two 5A11/Basigin transcripts of approximately 1.5 kb and approximately 1.8 kb, which correspond to glycosylated proteins of approximately 45 and approximately 55 kDa, respectively, were identified in mouse retina. The shorter form was previously cloned. However, the longer form, a splice variant of mouse 5A11/Basigin, is a member of the immunoglobulin gene superfamily and has been named 5A11/Basigin-2. Homologous transcripts were also cloned from rat, chicken, zebrafish, and human retina. 5A11/Basigin-2 expression was limited to the retina, specifically to photoreceptor cells, where it appeared to be most concentrated in the inner segments. CONCLUSIONS The specific and limited expression of 5A11/Basigin-2 explicitly within photoreceptor cells implies that this glycoprotein plays a fundamental role within the retina. However, its role remains to be determined.
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Retina-specific expression of 5A11/Basigin-2, a member of the immunoglobulin gene superfamily.
Investigative ophthalmology & visual science, 2003Co-Authors: Judith D. Ochrietor, Takashi Muramatsu, Tatiana P Moroz, Leslie Van Ekeris, Michael F Clamp, Stephanie C Jefferson, Ana C Decarvalho, James M Fadool, Graeme Wistow, Paul J LinserAbstract:PURPOSE 5A11/Basigin has recently been identified as a critical glycoprotein for full maturity and function of the mouse retina. However, the biological function of 5A11/Basigin has yet to be determined. Previous reports indicate the presence of multiple 5A11/Basigin polypeptides within the retina. Therefore, in an effort to determine the function of 5A11/Basigin, the molecular diversity of its expression was evaluated. METHODS Northern blot and immunoblot techniques were used to evaluate the number of forms of 5A11/Basigin in the mouse retina. cDNA cloning, using a mouse retina library or RT-PCR from rat, chicken, zebrafish, and human retina, was performed to determine the sequence of 5A11/Basigin transcripts. A peptide was generated, based on the deduced amino acid sequence, for subsequent antibody production. Localization of 5A11/Basigin expression was evaluated by immunoblot, immunohistochemistry, and real-time RT-PCR. RESULTS Two 5A11/Basigin transcripts of approximately 1.5 kb and approximately 1.8 kb, which correspond to glycosylated proteins of approximately 45 and approximately 55 kDa, respectively, were identified in mouse retina. The shorter form was previously cloned. However, the longer form, a splice variant of mouse 5A11/Basigin, is a member of the immunoglobulin gene superfamily and has been named 5A11/Basigin-2. Homologous transcripts were also cloned from rat, chicken, zebrafish, and human retina. 5A11/Basigin-2 expression was limited to the retina, specifically to photoreceptor cells, where it appeared to be most concentrated in the inner segments. CONCLUSIONS The specific and limited expression of 5A11/Basigin-2 explicitly within photoreceptor cells implies that this glycoprotein plays a fundamental role within the retina. However, its role remains to be determined.
Gavin J. Wright - One of the best experts on this subject based on the ideXlab platform.
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No evidence for Basigin/CD147 as a direct SARS-CoV-2 spike binding receptor.
Scientific reports, 2021Co-Authors: Jarrod Shilts, Thomas W. M. Crozier, Edward J. D. Greenwood, Paul J. Lehner, Gavin J. WrightAbstract:The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently proposed to be Basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses speculating on the role of this host receptor in viral infection and pathogenesis. Here, we report that we are unable to find evidence supporting the role of Basigin as a putative spike binding receptor. Recombinant forms of the SARS-CoV-2 spike do not interact with Basigin expressed on the surface of human cells, and by using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed Basigin-spike binding, we report no evidence for a direct interaction between the viral spike protein to either of the two common isoforms of Basigin. Finally, removing Basigin from the surface of human lung epithelial cells by CRISPR/Cas9 results in no change in their susceptibility to SARS-CoV-2 infection. Given the pressing need for clarity on which viral targets may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.
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no evidence for Basigin cd147 as a direct sars cov 2 spike binding receptor
Scientific Reports, 2021Co-Authors: Jarrod Shilts, Thomas W. M. Crozier, Edward J. D. Greenwood, Paul J. Lehner, Gavin J. WrightAbstract:The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently proposed to be Basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses speculating on the role of this host receptor in viral infection and pathogenesis. Here, we report that we are unable to find evidence supporting the role of Basigin as a putative spike binding receptor. Recombinant forms of the SARS-CoV-2 spike do not interact with Basigin expressed on the surface of human cells, and by using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed Basigin-spike binding, we report no evidence for a direct interaction between the viral spike protein to either of the two common isoforms of Basigin. Finally, removing Basigin from the surface of human lung epithelial cells by CRISPR/Cas9 results in no change in their susceptibility to SARS-CoV-2 infection. Given the pressing need for clarity on which viral targets may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.
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No evidence for Basigin/CD147 as a direct SARS-CoV-2 spike binding receptor
2020Co-Authors: Jarrod Shilts, Gavin J. WrightAbstract:Abstract The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently proposed to be Basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses of the role of this host receptor in viral infection and pathogenesis. We sought to independently characterize the Basigin-spike protein interaction. After conducting several lines of experiments, we report that we are unable to find evidence supporting the role of Basigin as a putative spike-binding receptor. Recombinant forms of both the entire ectodomain and S1 domain of the SARS-CoV-2 spike protein that directly bind ACE2 do not interact with Basigin expressed on the surface of human cells. Using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed Basigin-spike binding, we report no evidence for direct binding of the viral spike to either of the two common isoforms of Basigin. Given the pressing need for clarity on which targets of SARS-CoV-2 may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.
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no evidence for Basigin cd147 as a direct sars cov 2 spike binding receptor
bioRxiv, 2020Co-Authors: Jarrod Shilts, Gavin J. WrightAbstract:Abstract The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently proposed to be Basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses of the role of this host receptor in viral infection and pathogenesis. We sought to independently characterize the Basigin-spike protein interaction. After conducting several lines of experiments, we report that we are unable to find evidence supporting the role of Basigin as a putative spike-binding receptor. Recombinant forms of both the entire ectodomain and S1 domain of the SARS-CoV-2 spike protein that directly bind ACE2 do not interact with Basigin expressed on the surface of human cells. Using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed Basigin-spike binding, we report no evidence for direct binding of the viral spike to either of the two common isoforms of Basigin. Given the pressing need for clarity on which targets of SARS-CoV-2 may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.
Jacques Pouysségur - One of the best experts on this subject based on the ideXlab platform.
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Knock out of the Basigin/CD147 chaperone of lactate/H+ symporters disproves its pro-tumour action via extracellular matrix metalloproteases (MMPs) induction.
Oncotarget, 2015Co-Authors: Ibtissam Marchiq, Jean Albrengues, Sara Granja, Cedric Gaggioli, Jacques Pouysségur, Marie-pierre SimonAbstract:Basigin/CD147/EMMPRIN is a multifunctional transmembrane glycoprotein strongly expressed in tumours. Basigin controls tumour metabolism, particularly glycolysis by facilitating lactic acid export through the two monocarboxylate transporters MCT1 and hypoxia-inducible MCT4. However, before being recognized as a co-carrier of MCTs, Basigin was described as an inducer of extracellular matrix metalloproteases (MMPs). Early on, a model emerged in which, tumour cells use the extracellular domain of Basigin to recognize and stimulate neighbouring fibroblasts to produce MMPs. However, this model has remained hypothetical since a direct link between Basigin and MMPs production has not yet been clearly established. To validate the Basigin/MMP hypothesis, we developed Basigin knockouts in three human tumour cell lines derived from glioma, colon, and lung adenocarcinoma. By using co-culture experiments of either human or mouse fibroblasts and tumour cell lines we showed, contrary to what has been abundantly published, that the disruption of Basigin in tumour cells and in MEFs has no action on the production of MMPs. Our findings do not support the notion that the pro-tumoural action of Basigin is mediated via induction of MMPs. Therefore, we propose that to date, the strongest pro-tumoural action of Basigin is mediated through the control of fermentative glycolysis.
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knock out of the Basigin cd147 chaperone of lactate h symporters disproves its pro tumour action via extracellular matrix metalloproteases mmps induction
Oncotarget, 2015Co-Authors: Ibtissam Marchiq, Jean Albrengues, Sara Granja, Cedric Gaggioli, Jacques Pouysségur, Marie-pierre SimonAbstract:Basigin/CD147/EMMPRIN is a multifunctional transmembrane glycoprotein strongly expressed in tumours. Basigin controls tumour metabolism, particularly glycolysis by facilitating lactic acid export through the two monocarboxylate transporters MCT1 and hypoxia-inducible MCT4. However, before being recognized as a co-carrier of MCTs, Basigin was described as an inducer of extracellular matrix metalloproteases (MMPs). Early on, a model emerged in which, tumour cells use the extracellular domain of Basigin to recognize and stimulate neighbouring fibroblasts to produce MMPs. However, this model has remained hypothetical since a direct link between Basigin and MMPs production has not yet been clearly established. To validate the Basigin/MMP hypothesis, we developed Basigin knockouts in three human tumour cell lines derived from glioma, colon, and lung adenocarcinoma. By using co-culture experiments of either human or mouse fibroblasts and tumour cell lines we showed, contrary to what has been abundantly published, that the disruption of Basigin in tumour cells and in MEFs has no action on the production of MMPs. Our findings do not support the notion that the pro-tumoural action of Basigin is mediated via induction of MMPs. Therefore, we propose that to date, the strongest pro-tumoural action of Basigin is mediated through the control of fermentative glycolysis.
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Abstract 3225: Growth inhibition of glycolytic tumors by targeting Basigin/lactate-H+ symporters (MCTs): Metformin sensitizes MCT inhibition
Molecular and Cellular Biology, 2012Co-Authors: Renaud Le Floch, Ibtissam Marchiq, Marie-pierre Simon, Johanna Chiche, Tanesha Naïken, Danièle Roux, Karine Ilc, Jacques PouysségurAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Intense conversion of glucose to lactic acid via glycolysis is a feature of rapidly growing cells often encountered in hypoxic tumor microenvironments. To survive and expand, tumor cells must efficiently export lactic acid to maintain intracellular pH. Cells possess several systems for lactic acid extrusion. A family of H+-linked MonoCarboxylate Transporters (MCTs) is represented by the ubiquitously expressed MCT1, a H+/lactate symporter that operates in both directions. MCT4, a close relative of MCT1, is up-regulated by HIF-1 and is highly expressed in aggressive malignant tumors. In addition, the functional expression of MCT1/MCT4 requires the interaction with the glycoprotein CD147/Basigin also known as EMMPRIN, a protumoral protein involved in invasion. Objectives: 1) Demonstrate that tumor growth is dependent on lactic acid export and that both transporters MCT1/MCT4 represent key anticancer targets. 2) Demonstrate whether the protumoral function of Basigin/CD147 is primary linked to lactic acid export or to other invasive functions. 3) Demonstrate whether Metformin, an inhibitor of mitochondrial complex I, sensitizes glycolytic tumor cells to MCTs inhibitors. Methods: We exploited two tumoral models. i) Ras transformed fibroblasts expressing only MCT1/MCT2 and ii) the human colon adenocarcinoma cell line LS174T expressing MCT1 and MCT4. We inhibited MCT1/MCT2 with the specific astraZeneca compound AR-C155858 and knocked-down MCT1, MCT4 and CD147 with inducible shRNAs. In addition we knocked-out mct4 or Basigin with Zinc Finger Nucleases in LS174T cells. Results: First we demonstrated that silencing or pharmacological blockage of MCTs, reduced pHi, the rate of glycolysis and tumor growth in mice xenografts. This tumor growth inhibition was recapitulated by a single silencing or knock out of Basigin/CD147 gene that also reduced the plasma membrane expression of MCT1 and MCT4 and lactate transport up to 10-fold. Second, to gain insight into CD147/Basigin function, we uncoupled MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin-high expressors, suppressed tumor growth. Conversely in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Thirdly, we showed that tumor cells lacking Basigin or MCT4 become highly sensitive to MCT1 inhibition when treated with Metformin. This synthetic lethality demonstrated in vitro and currently being tested in vivo will be discussed. Conclusions: These findings highlight that a major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer approach. Furthermore, we reveal that Metformin, by sensitizing normoxic cells to inhibitors of lactic export (MCTs), could offer an interesting novel anticancer strategy for rapidly growing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3225. doi:1538-7445.AM2012-3225
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abstract 3225 growth inhibition of glycolytic tumors by targeting Basigin lactate h symporters mcts metformin sensitizes mct inhibition
Cancer Research, 2012Co-Authors: Renaud Le Floch, Ibtissam Marchiq, Marie-pierre Simon, Johanna Chiche, Tanesha Naïken, Danièle Roux, Karine Ilc, Jacques PouysségurAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Intense conversion of glucose to lactic acid via glycolysis is a feature of rapidly growing cells often encountered in hypoxic tumor microenvironments. To survive and expand, tumor cells must efficiently export lactic acid to maintain intracellular pH. Cells possess several systems for lactic acid extrusion. A family of H+-linked MonoCarboxylate Transporters (MCTs) is represented by the ubiquitously expressed MCT1, a H+/lactate symporter that operates in both directions. MCT4, a close relative of MCT1, is up-regulated by HIF-1 and is highly expressed in aggressive malignant tumors. In addition, the functional expression of MCT1/MCT4 requires the interaction with the glycoprotein CD147/Basigin also known as EMMPRIN, a protumoral protein involved in invasion. Objectives: 1) Demonstrate that tumor growth is dependent on lactic acid export and that both transporters MCT1/MCT4 represent key anticancer targets. 2) Demonstrate whether the protumoral function of Basigin/CD147 is primary linked to lactic acid export or to other invasive functions. 3) Demonstrate whether Metformin, an inhibitor of mitochondrial complex I, sensitizes glycolytic tumor cells to MCTs inhibitors. Methods: We exploited two tumoral models. i) Ras transformed fibroblasts expressing only MCT1/MCT2 and ii) the human colon adenocarcinoma cell line LS174T expressing MCT1 and MCT4. We inhibited MCT1/MCT2 with the specific astraZeneca compound AR-C155858 and knocked-down MCT1, MCT4 and CD147 with inducible shRNAs. In addition we knocked-out mct4 or Basigin with Zinc Finger Nucleases in LS174T cells. Results: First we demonstrated that silencing or pharmacological blockage of MCTs, reduced pHi, the rate of glycolysis and tumor growth in mice xenografts. This tumor growth inhibition was recapitulated by a single silencing or knock out of Basigin/CD147 gene that also reduced the plasma membrane expression of MCT1 and MCT4 and lactate transport up to 10-fold. Second, to gain insight into CD147/Basigin function, we uncoupled MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin-high expressors, suppressed tumor growth. Conversely in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Thirdly, we showed that tumor cells lacking Basigin or MCT4 become highly sensitive to MCT1 inhibition when treated with Metformin. This synthetic lethality demonstrated in vitro and currently being tested in vivo will be discussed. Conclusions: These findings highlight that a major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer approach. Furthermore, we reveal that Metformin, by sensitizing normoxic cells to inhibitors of lactic export (MCTs), could offer an interesting novel anticancer strategy for rapidly growing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3225. doi:1538-7445.AM2012-3225
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CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors.
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Renaud Le Floch, Ibtissam Marchiq, Marie-pierre Simon, Johanna Chiche, Tanesha Naïken, Karine Ilk, Clare M Murray, Susan E Critchlow, Danièle Roux, Jacques PouysségurAbstract:Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step in tumorigenesis. Lactic acid is mainly transported by two H(+)/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed that blocking MCT1/2 in Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, glycolysis, and tumor growth, whereas ectopic expression of MCT4 in these cells conferred resistance to MCT1/2 inhibition and reestablished tumorigenicty. A mutant-derivative, deficient in respiration (res(-)) and exclusively relying on glycolysis for energy, displayed low tumorigenicity. These res(-) cells could develop resistance to MCT1/2 inhibition and became highly tumorigenic by reactivating their endogenous mct4 gene, highlighting that MCT4, the hypoxia-inducible and tumor-associated lactate/H(+) symporter, drives tumorigenicity. Second, in the human colon adenocarcinoma cell line (LS174T), we showed that combined silencing of MCT1/MCT4 via inducible shRNA, or silencing of CD147/Basigin alone, significantly reduced glycolytic flux and tumor growth. However, both silencing approaches, which reduced tumor growth, displayed a low level of CD147/Basigin, a multifunctional protumoral protein. To gain insight into CD147/Basigin function, we designed experiments, via zinc finger nuclease-mediated mct4 and Basigin knockouts, to uncouple MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin(high) cells suppressed tumor growth. Conversely, in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Collectively, these findings highlight that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer strategy.
Marie-pierre Simon - One of the best experts on this subject based on the ideXlab platform.
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Knock out of the Basigin/CD147 chaperone of lactate/H+ symporters disproves its pro-tumour action via extracellular matrix metalloproteases (MMPs) induction.
Oncotarget, 2015Co-Authors: Ibtissam Marchiq, Jean Albrengues, Sara Granja, Cedric Gaggioli, Jacques Pouysségur, Marie-pierre SimonAbstract:Basigin/CD147/EMMPRIN is a multifunctional transmembrane glycoprotein strongly expressed in tumours. Basigin controls tumour metabolism, particularly glycolysis by facilitating lactic acid export through the two monocarboxylate transporters MCT1 and hypoxia-inducible MCT4. However, before being recognized as a co-carrier of MCTs, Basigin was described as an inducer of extracellular matrix metalloproteases (MMPs). Early on, a model emerged in which, tumour cells use the extracellular domain of Basigin to recognize and stimulate neighbouring fibroblasts to produce MMPs. However, this model has remained hypothetical since a direct link between Basigin and MMPs production has not yet been clearly established. To validate the Basigin/MMP hypothesis, we developed Basigin knockouts in three human tumour cell lines derived from glioma, colon, and lung adenocarcinoma. By using co-culture experiments of either human or mouse fibroblasts and tumour cell lines we showed, contrary to what has been abundantly published, that the disruption of Basigin in tumour cells and in MEFs has no action on the production of MMPs. Our findings do not support the notion that the pro-tumoural action of Basigin is mediated via induction of MMPs. Therefore, we propose that to date, the strongest pro-tumoural action of Basigin is mediated through the control of fermentative glycolysis.
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knock out of the Basigin cd147 chaperone of lactate h symporters disproves its pro tumour action via extracellular matrix metalloproteases mmps induction
Oncotarget, 2015Co-Authors: Ibtissam Marchiq, Jean Albrengues, Sara Granja, Cedric Gaggioli, Jacques Pouysségur, Marie-pierre SimonAbstract:Basigin/CD147/EMMPRIN is a multifunctional transmembrane glycoprotein strongly expressed in tumours. Basigin controls tumour metabolism, particularly glycolysis by facilitating lactic acid export through the two monocarboxylate transporters MCT1 and hypoxia-inducible MCT4. However, before being recognized as a co-carrier of MCTs, Basigin was described as an inducer of extracellular matrix metalloproteases (MMPs). Early on, a model emerged in which, tumour cells use the extracellular domain of Basigin to recognize and stimulate neighbouring fibroblasts to produce MMPs. However, this model has remained hypothetical since a direct link between Basigin and MMPs production has not yet been clearly established. To validate the Basigin/MMP hypothesis, we developed Basigin knockouts in three human tumour cell lines derived from glioma, colon, and lung adenocarcinoma. By using co-culture experiments of either human or mouse fibroblasts and tumour cell lines we showed, contrary to what has been abundantly published, that the disruption of Basigin in tumour cells and in MEFs has no action on the production of MMPs. Our findings do not support the notion that the pro-tumoural action of Basigin is mediated via induction of MMPs. Therefore, we propose that to date, the strongest pro-tumoural action of Basigin is mediated through the control of fermentative glycolysis.
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Abstract 3225: Growth inhibition of glycolytic tumors by targeting Basigin/lactate-H+ symporters (MCTs): Metformin sensitizes MCT inhibition
Molecular and Cellular Biology, 2012Co-Authors: Renaud Le Floch, Ibtissam Marchiq, Marie-pierre Simon, Johanna Chiche, Tanesha Naïken, Danièle Roux, Karine Ilc, Jacques PouysségurAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Intense conversion of glucose to lactic acid via glycolysis is a feature of rapidly growing cells often encountered in hypoxic tumor microenvironments. To survive and expand, tumor cells must efficiently export lactic acid to maintain intracellular pH. Cells possess several systems for lactic acid extrusion. A family of H+-linked MonoCarboxylate Transporters (MCTs) is represented by the ubiquitously expressed MCT1, a H+/lactate symporter that operates in both directions. MCT4, a close relative of MCT1, is up-regulated by HIF-1 and is highly expressed in aggressive malignant tumors. In addition, the functional expression of MCT1/MCT4 requires the interaction with the glycoprotein CD147/Basigin also known as EMMPRIN, a protumoral protein involved in invasion. Objectives: 1) Demonstrate that tumor growth is dependent on lactic acid export and that both transporters MCT1/MCT4 represent key anticancer targets. 2) Demonstrate whether the protumoral function of Basigin/CD147 is primary linked to lactic acid export or to other invasive functions. 3) Demonstrate whether Metformin, an inhibitor of mitochondrial complex I, sensitizes glycolytic tumor cells to MCTs inhibitors. Methods: We exploited two tumoral models. i) Ras transformed fibroblasts expressing only MCT1/MCT2 and ii) the human colon adenocarcinoma cell line LS174T expressing MCT1 and MCT4. We inhibited MCT1/MCT2 with the specific astraZeneca compound AR-C155858 and knocked-down MCT1, MCT4 and CD147 with inducible shRNAs. In addition we knocked-out mct4 or Basigin with Zinc Finger Nucleases in LS174T cells. Results: First we demonstrated that silencing or pharmacological blockage of MCTs, reduced pHi, the rate of glycolysis and tumor growth in mice xenografts. This tumor growth inhibition was recapitulated by a single silencing or knock out of Basigin/CD147 gene that also reduced the plasma membrane expression of MCT1 and MCT4 and lactate transport up to 10-fold. Second, to gain insight into CD147/Basigin function, we uncoupled MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin-high expressors, suppressed tumor growth. Conversely in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Thirdly, we showed that tumor cells lacking Basigin or MCT4 become highly sensitive to MCT1 inhibition when treated with Metformin. This synthetic lethality demonstrated in vitro and currently being tested in vivo will be discussed. Conclusions: These findings highlight that a major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer approach. Furthermore, we reveal that Metformin, by sensitizing normoxic cells to inhibitors of lactic export (MCTs), could offer an interesting novel anticancer strategy for rapidly growing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3225. doi:1538-7445.AM2012-3225
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abstract 3225 growth inhibition of glycolytic tumors by targeting Basigin lactate h symporters mcts metformin sensitizes mct inhibition
Cancer Research, 2012Co-Authors: Renaud Le Floch, Ibtissam Marchiq, Marie-pierre Simon, Johanna Chiche, Tanesha Naïken, Danièle Roux, Karine Ilc, Jacques PouysségurAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Intense conversion of glucose to lactic acid via glycolysis is a feature of rapidly growing cells often encountered in hypoxic tumor microenvironments. To survive and expand, tumor cells must efficiently export lactic acid to maintain intracellular pH. Cells possess several systems for lactic acid extrusion. A family of H+-linked MonoCarboxylate Transporters (MCTs) is represented by the ubiquitously expressed MCT1, a H+/lactate symporter that operates in both directions. MCT4, a close relative of MCT1, is up-regulated by HIF-1 and is highly expressed in aggressive malignant tumors. In addition, the functional expression of MCT1/MCT4 requires the interaction with the glycoprotein CD147/Basigin also known as EMMPRIN, a protumoral protein involved in invasion. Objectives: 1) Demonstrate that tumor growth is dependent on lactic acid export and that both transporters MCT1/MCT4 represent key anticancer targets. 2) Demonstrate whether the protumoral function of Basigin/CD147 is primary linked to lactic acid export or to other invasive functions. 3) Demonstrate whether Metformin, an inhibitor of mitochondrial complex I, sensitizes glycolytic tumor cells to MCTs inhibitors. Methods: We exploited two tumoral models. i) Ras transformed fibroblasts expressing only MCT1/MCT2 and ii) the human colon adenocarcinoma cell line LS174T expressing MCT1 and MCT4. We inhibited MCT1/MCT2 with the specific astraZeneca compound AR-C155858 and knocked-down MCT1, MCT4 and CD147 with inducible shRNAs. In addition we knocked-out mct4 or Basigin with Zinc Finger Nucleases in LS174T cells. Results: First we demonstrated that silencing or pharmacological blockage of MCTs, reduced pHi, the rate of glycolysis and tumor growth in mice xenografts. This tumor growth inhibition was recapitulated by a single silencing or knock out of Basigin/CD147 gene that also reduced the plasma membrane expression of MCT1 and MCT4 and lactate transport up to 10-fold. Second, to gain insight into CD147/Basigin function, we uncoupled MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin-high expressors, suppressed tumor growth. Conversely in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Thirdly, we showed that tumor cells lacking Basigin or MCT4 become highly sensitive to MCT1 inhibition when treated with Metformin. This synthetic lethality demonstrated in vitro and currently being tested in vivo will be discussed. Conclusions: These findings highlight that a major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer approach. Furthermore, we reveal that Metformin, by sensitizing normoxic cells to inhibitors of lactic export (MCTs), could offer an interesting novel anticancer strategy for rapidly growing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3225. doi:1538-7445.AM2012-3225
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CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors.
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Renaud Le Floch, Ibtissam Marchiq, Marie-pierre Simon, Johanna Chiche, Tanesha Naïken, Karine Ilk, Clare M Murray, Susan E Critchlow, Danièle Roux, Jacques PouysségurAbstract:Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step in tumorigenesis. Lactic acid is mainly transported by two H(+)/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed that blocking MCT1/2 in Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, glycolysis, and tumor growth, whereas ectopic expression of MCT4 in these cells conferred resistance to MCT1/2 inhibition and reestablished tumorigenicty. A mutant-derivative, deficient in respiration (res(-)) and exclusively relying on glycolysis for energy, displayed low tumorigenicity. These res(-) cells could develop resistance to MCT1/2 inhibition and became highly tumorigenic by reactivating their endogenous mct4 gene, highlighting that MCT4, the hypoxia-inducible and tumor-associated lactate/H(+) symporter, drives tumorigenicity. Second, in the human colon adenocarcinoma cell line (LS174T), we showed that combined silencing of MCT1/MCT4 via inducible shRNA, or silencing of CD147/Basigin alone, significantly reduced glycolytic flux and tumor growth. However, both silencing approaches, which reduced tumor growth, displayed a low level of CD147/Basigin, a multifunctional protumoral protein. To gain insight into CD147/Basigin function, we designed experiments, via zinc finger nuclease-mediated mct4 and Basigin knockouts, to uncouple MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin(high) cells suppressed tumor growth. Conversely, in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Collectively, these findings highlight that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer strategy.