The Experts below are selected from a list of 972 Experts worldwide ranked by ideXlab platform

Paul-alain Jaffres - One of the best experts on this subject based on the ideXlab platform.

  • Singular Interaction between an Antimetastatic Agent and the Lipid Bilayer: The Ohmline Case.
    ACS Omega, 2017
    Co-Authors: Fernando Herrera, Aurelie Chantome, Paul-alain Jaffres, Charlotte M. Sevrain, Hélène Couthon, Axelle Grélard, Erick J. Dufourc, Marie Potier-cartereau, Christophe Vandier, Ana Bouchet
    Abstract:

    SK3 channels are abnormaly expressed in metastatic cells, and Ohmline (OHM), an ether lipid, has been shown to reduce the activity of SK3 channels and the migration capacity of cancer cells. OHM incorporation into the plasma membrane is proposed to dissociate the protein complex formed between SK3 and Orai1, a potassium and a calcium channel, respectively, and would lead to a modification in the lipid environment of both the proteins. Here, we report the synthesis of deuterated OHM that affords the determination, through solid-state NMR, of its entire partitioning into membranes mimicking the SK3 environment. Use of deuterated lipids affords the demonstration of an OHM-induced membrane disordering, which is dose-dependent and increases with increasing amounts of cholesterol (CHOL). Molecular dynamics simulations comfort the disordering action and show that OHM interacts with the carbonyl and phosphate groups of stearoylphosphatidylcholine and sphingomyelin and to a minor extent with CHOL. OHM is thus prop...

  • New alkyl-lipid blockers of SK3 channels reduce cancer-cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Thibauld Oullier, Jeanpierre Haelters, Michelle Pinault, Aurelie Chantome, Hélène Couthon, Marie Potier-cartereau, Severine Marionneau-lambot, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel-mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl-2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamine from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

  • new alkyl lipid blockers of sk3 channels reduce cancer cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Marie Potiercartereau, Severine Marionneaulambot, Thibauld Oullier, Jeanpierre Haelters, Helene Couthongourves, Michelle Pinault, Aurelie Chantome, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel – mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

  • new alkyl lipid blockers of sk3 channels reduce cancer cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Marie Potiercartereau, Severine Marionneaulambot, Thibauld Oullier, Jeanpierre Haelters, Helene Couthongourves, Michelle Pinault, Aurelie Chantome, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel – mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

Hiroshi Sato - One of the best experts on this subject based on the ideXlab platform.

  • cleavage of metastasis suppressor gene product kiss 1 protein metastin by matrix metalloproteinases
    Oncogene, 2003
    Co-Authors: Takahisa Takino, Naohiko Koshikawa, Hisashi Miyamori, Motohiro Tanaka, Takuma Sasaki, Yasunori Okada, Motoharu Seiki, Hiroshi Sato
    Abstract:

    A human placenta cDNA library was screened by the expression cloning method for gene products that interact with matrix metalloproteinases (MMPs), and we isolated a cDNA whose product formed a stable complex with pro-MMP-2 and pro-MMP-9. The cDNA encoded the metastasis suppressor gene KiSS-1. KiSS-1 protein was shown to form a complex with pro-MMP. KiSS-1 protein is known to be processed to peptide ligand of a G-protein-coupled receptor (hOT7T175) named metastin, and suppresses metastasis of tumors expressing the receptor. Active MMP-2, MMP-9, MT1-MMP, MT3-MMP and MT5-MMP cleaved the Gly118-Leu119 peptide bond of not only full-length KiSS-1 protein but also metastin decapeptide. Metastin decapeptide induced formation of focal adhesion and actin stress fibers in cells expressing the receptor, and digestion of metastin decapeptide by MMP abolished its ligand activity. Migration of HT1080 cells expressing hOT7T175 that harbor a high-level MMP activity was only slightly suppressed by either metastin decapeptide or MMP inhibitor BB-94 alone, but the combination of metastin decapeptide and BB-94 showed a synergistic effect in blocking cell migration. We propose that metastin could be used as an Antimetastatic Agent in combination with MMP inhibitor, or MMP-resistant forms of metastin could be developed and may also be efficacious.

  • Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases
    Oncogene, 2003
    Co-Authors: Takahisa Takino, Naohiko Koshikawa, Hisashi Miyamori, Motohiro Tanaka, Takuma Sasaki, Yasunori Okada, Motoharu Seiki, Hiroshi Sato
    Abstract:

    A human placenta cDNA library was screened by the expression cloning method for gene products that interact with matrix metalloproteinases (MMPs), and we isolated a cDNA whose product formed a stable complex with pro-MMP-2 and pro-MMP-9. The cDNA encoded the metastasis suppressor gene KiSS-1 . KiSS-1 protein was shown to form a complex with pro-MMP. KiSS-1 protein is known to be processed to peptide ligand of a G-protein-coupled receptor (hOT7T175) named metastin, and suppresses metastasis of tumors expressing the receptor. Active MMP-2, MMP-9, MT1-MMP, MT3-MMP and MT5-MMP cleaved the Gly^118-Leu^119 peptide bond of not only full-length KiSS-1 protein but also metastin decapeptide. Metastin decapeptide induced formation of focal adhesion and actin stress fibers in cells expressing the receptor, and digestion of metastin decapeptide by MMP abolished its ligand activity. Migration of HT1080 cells expressing hOT7T175 that harbor a high-level MMP activity was only slightly suppressed by either metastin decapeptide or MMP inhibitor BB-94 alone, but the combination of metastin decapeptide and BB-94 showed a synergistic effect in blocking cell migration. We propose that metastin could be used as an Antimetastatic Agent in combination with MMP inhibitor, or MMP-resistant forms of metastin could be developed and may also be efficacious.

Alban Girault - One of the best experts on this subject based on the ideXlab platform.

  • New alkyl-lipid blockers of SK3 channels reduce cancer-cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Thibauld Oullier, Jeanpierre Haelters, Michelle Pinault, Aurelie Chantome, Hélène Couthon, Marie Potier-cartereau, Severine Marionneau-lambot, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel-mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl-2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamine from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

  • new alkyl lipid blockers of sk3 channels reduce cancer cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Marie Potiercartereau, Severine Marionneaulambot, Thibauld Oullier, Jeanpierre Haelters, Helene Couthongourves, Michelle Pinault, Aurelie Chantome, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel – mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

  • new alkyl lipid blockers of sk3 channels reduce cancer cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Marie Potiercartereau, Severine Marionneaulambot, Thibauld Oullier, Jeanpierre Haelters, Helene Couthongourves, Michelle Pinault, Aurelie Chantome, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel – mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

Aurelie Chantome - One of the best experts on this subject based on the ideXlab platform.

  • Singular Interaction between an Antimetastatic Agent and the Lipid Bilayer: The Ohmline Case.
    ACS Omega, 2017
    Co-Authors: Fernando Herrera, Aurelie Chantome, Paul-alain Jaffres, Charlotte M. Sevrain, Hélène Couthon, Axelle Grélard, Erick J. Dufourc, Marie Potier-cartereau, Christophe Vandier, Ana Bouchet
    Abstract:

    SK3 channels are abnormaly expressed in metastatic cells, and Ohmline (OHM), an ether lipid, has been shown to reduce the activity of SK3 channels and the migration capacity of cancer cells. OHM incorporation into the plasma membrane is proposed to dissociate the protein complex formed between SK3 and Orai1, a potassium and a calcium channel, respectively, and would lead to a modification in the lipid environment of both the proteins. Here, we report the synthesis of deuterated OHM that affords the determination, through solid-state NMR, of its entire partitioning into membranes mimicking the SK3 environment. Use of deuterated lipids affords the demonstration of an OHM-induced membrane disordering, which is dose-dependent and increases with increasing amounts of cholesterol (CHOL). Molecular dynamics simulations comfort the disordering action and show that OHM interacts with the carbonyl and phosphate groups of stearoylphosphatidylcholine and sphingomyelin and to a minor extent with CHOL. OHM is thus prop...

  • New alkyl-lipid blockers of SK3 channels reduce cancer-cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Thibauld Oullier, Jeanpierre Haelters, Michelle Pinault, Aurelie Chantome, Hélène Couthon, Marie Potier-cartereau, Severine Marionneau-lambot, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel-mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl-2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamine from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

  • new alkyl lipid blockers of sk3 channels reduce cancer cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Marie Potiercartereau, Severine Marionneaulambot, Thibauld Oullier, Jeanpierre Haelters, Helene Couthongourves, Michelle Pinault, Aurelie Chantome, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel – mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

  • new alkyl lipid blockers of sk3 channels reduce cancer cell migration and occurrence of metastasis
    Current Cancer Drug Targets, 2011
    Co-Authors: Alban Girault, Gaëlle Simon, Marie Potiercartereau, Severine Marionneaulambot, Thibauld Oullier, Jeanpierre Haelters, Helene Couthongourves, Michelle Pinault, Aurelie Chantome, Paul-alain Jaffres
    Abstract:

    Edelfosine is an inhibitor of SK3 channel – mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-Antimetastatic Agent.

Takahisa Takino - One of the best experts on this subject based on the ideXlab platform.

  • cleavage of metastasis suppressor gene product kiss 1 protein metastin by matrix metalloproteinases
    Oncogene, 2003
    Co-Authors: Takahisa Takino, Naohiko Koshikawa, Hisashi Miyamori, Motohiro Tanaka, Takuma Sasaki, Yasunori Okada, Motoharu Seiki, Hiroshi Sato
    Abstract:

    A human placenta cDNA library was screened by the expression cloning method for gene products that interact with matrix metalloproteinases (MMPs), and we isolated a cDNA whose product formed a stable complex with pro-MMP-2 and pro-MMP-9. The cDNA encoded the metastasis suppressor gene KiSS-1. KiSS-1 protein was shown to form a complex with pro-MMP. KiSS-1 protein is known to be processed to peptide ligand of a G-protein-coupled receptor (hOT7T175) named metastin, and suppresses metastasis of tumors expressing the receptor. Active MMP-2, MMP-9, MT1-MMP, MT3-MMP and MT5-MMP cleaved the Gly118-Leu119 peptide bond of not only full-length KiSS-1 protein but also metastin decapeptide. Metastin decapeptide induced formation of focal adhesion and actin stress fibers in cells expressing the receptor, and digestion of metastin decapeptide by MMP abolished its ligand activity. Migration of HT1080 cells expressing hOT7T175 that harbor a high-level MMP activity was only slightly suppressed by either metastin decapeptide or MMP inhibitor BB-94 alone, but the combination of metastin decapeptide and BB-94 showed a synergistic effect in blocking cell migration. We propose that metastin could be used as an Antimetastatic Agent in combination with MMP inhibitor, or MMP-resistant forms of metastin could be developed and may also be efficacious.

  • Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases
    Oncogene, 2003
    Co-Authors: Takahisa Takino, Naohiko Koshikawa, Hisashi Miyamori, Motohiro Tanaka, Takuma Sasaki, Yasunori Okada, Motoharu Seiki, Hiroshi Sato
    Abstract:

    A human placenta cDNA library was screened by the expression cloning method for gene products that interact with matrix metalloproteinases (MMPs), and we isolated a cDNA whose product formed a stable complex with pro-MMP-2 and pro-MMP-9. The cDNA encoded the metastasis suppressor gene KiSS-1 . KiSS-1 protein was shown to form a complex with pro-MMP. KiSS-1 protein is known to be processed to peptide ligand of a G-protein-coupled receptor (hOT7T175) named metastin, and suppresses metastasis of tumors expressing the receptor. Active MMP-2, MMP-9, MT1-MMP, MT3-MMP and MT5-MMP cleaved the Gly^118-Leu^119 peptide bond of not only full-length KiSS-1 protein but also metastin decapeptide. Metastin decapeptide induced formation of focal adhesion and actin stress fibers in cells expressing the receptor, and digestion of metastin decapeptide by MMP abolished its ligand activity. Migration of HT1080 cells expressing hOT7T175 that harbor a high-level MMP activity was only slightly suppressed by either metastin decapeptide or MMP inhibitor BB-94 alone, but the combination of metastin decapeptide and BB-94 showed a synergistic effect in blocking cell migration. We propose that metastin could be used as an Antimetastatic Agent in combination with MMP inhibitor, or MMP-resistant forms of metastin could be developed and may also be efficacious.