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Paul B Fisher - One of the best experts on this subject based on the ideXlab platform.

  • suppression of prostate cancer pathogenesis using an mda 9 Syntenin sdcbp pdz1 small molecule inhibitor
    Molecular Cancer Therapeutics, 2019
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xuening Shen, Timothy P Kegelman, Santanu Maji, Paul B Fisher
    Abstract:

    Metastasis is the primary determinant of death in patients with diverse solid tumors and MDA-9/Syntenin (SDCBP), a pro-metastatic and pro-angiogenic gene, contributes to this process. Recently, we documented that by physically interacting with IGF-1R, MDA-9/Syntenin activates STAT3 and regulates prostate cancer pathogenesis. These observations firmly established MDA-9/Syntenin as a potential molecular target in prostate cancer. MDA-9/Syntenin contains two highly homologous PDZ domains predicted to interact with a plethora of proteins, many of which are central to the cancerous process. An MDA-9/Syntenin PDZ1 domain-targeted small molecule (PDZ1i) was previously developed using fragment-based drug discovery (FBDD) guided by NMR spectroscopy and was found to be well-tolerated in vivo, had significant half-life (t1/2 = 9 hours) and displayed substantial anti-prostate cancer preclinical in vivo activity. PDZ1i blocked tumor cell invasion and migration in vitro, and metastasis in vivo. Hence, we demonstrate that PDZ1i an MDA-9/Syntenin PDZ1 target-specific small-molecule inhibitor displays therapeutic potential for prostate and potentially other cancers expressing elevated levels of MDA-9/Syntenin.

  • mda 9 Syntenin an emerging global molecular target regulating cancer invasion and metastasis
    Advances in Cancer Research, 2019
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Paul B Fisher
    Abstract:

    With few exceptions, metastasis is the terminal stage of cancer with limited therapeutic options. Metastasis consists of numerous phenotypic and genotypic alterations of cells that are directly and indirectly induced by multiple intrinsic (cellular) and extrinsic (micro-environmental) factors. To metastasize, a cancer cell often transitions from an epithelial to mesenchymal morphology (EMT), modifies the extracellular matrix, forms emboli and survives in the circulation, escapes immune surveillance, adheres to sites distant from the initial tumor and finally develops a blood supply (angiogenesis) and colonizes in a secondary niche (a micrometastasis). Scientific advances have greatly enhanced our understanding of the precise molecular and genetic changes, operating independently or collectively, that lead to metastasis. This review focuses on a unique gene, melanoma differentiation associated gene-9 (also known as Syntenin-1; Syndecan Binding Protein (sdcbp); mda-9/Syntenin), initially cloned and characterized from metastatic human melanoma and shown to be a pro-metastatic gene. In the last two decades, our comprehension of the diversity of actions of MDA-9/Syntenin on cellular phenotype has emerged. MDA-9/Sytenin plays pivotal regulatory roles in multiple signaling cascades and orchestrates both metastatic and non-metastatic events. Considering the relevance of this gene in controlling cancer invasion and metastasis, approaches have been developed to uniquely and selectively target this gene. We also provide recent updates on strategies that have been successfully employed in targeting MDA-9/Syntenin resulting in profound pre-clinical anti-cancer activity.

  • the mda 9 Syntenin igf1r stat3 axis directs prostate cancer invasion
    Cancer Research, 2018
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xuening Shen, Paul B Fisher
    Abstract:

    Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [Syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/Syntenin-manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/Syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/Syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers.Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852-63. ©2018 AACR.

  • targeting tumor invasion the roles of mda 9 Syntenin
    Expert Opinion on Therapeutic Targets, 2015
    Co-Authors: Timothy P Kegelman, Swadesh K Das, Devanand Sarkar, Luni Emdad, Mitchell E Menezes, Praveen Bhoopathi, Xiangyang Wang, Maurizio Pellecchia, Paul B Fisher
    Abstract:

    Introduction: Melanoma differentiation-associated gene – 9 (MDA-9)/Syntenin has become an increasingly popular focus for investigation in numerous cancertypes. Originally implicated in melanoma metastasis, it has diverse cellular roles and is consistently identified as a regulator of tumor invasion and angiogenesis. As a potential target for inhibiting some of the most lethal aspects of cancer progression, further insight into the function of MDA-9/Syntenin is mandatory.Areas covered: Recent literature and seminal articles were reviewed to summarize the latest collective understanding of MDA-9/Syntenin’s role in normal and cancerous settings. Insights into its participation in developmental processes are included, as is the functional significance of the N- and C-terminals and PDZ domains of MDA-9/Syntenin. Current reports highlight the clinical significance of MDA-9/Syntenin expression level in a variety of cancers, often correlating directly with reduced patient survival. Also presented are assessments ...

  • novel role of mda 9 Syntenin in regulating urothelial cell proliferation by modulating egfr signaling
    Clinical Cancer Research, 2013
    Co-Authors: Santanu Dasgupta, Swadesh K Das, Devanand Sarkar, Luni Emdad, Shilpa Bhatia, Mitchell E Menezes, Aleksandar Janjic, Nitai Mukhopadhyay, Chunbo Shao, Paul B Fisher
    Abstract:

    Purpose: Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression. Experimental Design: Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knockdown was examined in multiple cells lines and key findings were validated in primary tumors. Results: Significantly higher ( P = 0.002–0.003) expression of MDA-9/Syntenin was observed in 64% (28 of 44) of primary tumors and an association was evident with stage ( P = 0.01), grade ( P = 0.03), and invasion status ( P = 0.02). MDA-9/Syntenin overexpression in nontumorigenic HUC-1 cells increased proliferation ( P = 0.0012), invasion ( P = 0.0001), and EGF receptor (EGFR), AKT, phosphoinositide 3-kinase (PI3K), and c-Src expression. Alteration of β-catenin, E-cadherin, vimentin, claudin-1, ZO-1, and T-cell factor-4 (TCF4) expression was also observed. MDA-9/Syntenin knockdown in three UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and colocalization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin:AKT expressions with stage ( P = 0.04, EGFR; P = 0.01, AKT). A correlation between MDA-9/Syntenin:β-catenin coexpression with stage ( P = 0.03) and invasion ( P = 0.04) was also evident. Conclusions: Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring, and therapeutic strategies for managing UCC. Clin Cancer Res; 19(17); 4621–33. ©2013 AACR .

Devanand Sarkar - One of the best experts on this subject based on the ideXlab platform.

  • suppression of prostate cancer pathogenesis using an mda 9 Syntenin sdcbp pdz1 small molecule inhibitor
    Molecular Cancer Therapeutics, 2019
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xuening Shen, Timothy P Kegelman, Santanu Maji, Paul B Fisher
    Abstract:

    Metastasis is the primary determinant of death in patients with diverse solid tumors and MDA-9/Syntenin (SDCBP), a pro-metastatic and pro-angiogenic gene, contributes to this process. Recently, we documented that by physically interacting with IGF-1R, MDA-9/Syntenin activates STAT3 and regulates prostate cancer pathogenesis. These observations firmly established MDA-9/Syntenin as a potential molecular target in prostate cancer. MDA-9/Syntenin contains two highly homologous PDZ domains predicted to interact with a plethora of proteins, many of which are central to the cancerous process. An MDA-9/Syntenin PDZ1 domain-targeted small molecule (PDZ1i) was previously developed using fragment-based drug discovery (FBDD) guided by NMR spectroscopy and was found to be well-tolerated in vivo, had significant half-life (t1/2 = 9 hours) and displayed substantial anti-prostate cancer preclinical in vivo activity. PDZ1i blocked tumor cell invasion and migration in vitro, and metastasis in vivo. Hence, we demonstrate that PDZ1i an MDA-9/Syntenin PDZ1 target-specific small-molecule inhibitor displays therapeutic potential for prostate and potentially other cancers expressing elevated levels of MDA-9/Syntenin.

  • mda 9 Syntenin an emerging global molecular target regulating cancer invasion and metastasis
    Advances in Cancer Research, 2019
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Paul B Fisher
    Abstract:

    With few exceptions, metastasis is the terminal stage of cancer with limited therapeutic options. Metastasis consists of numerous phenotypic and genotypic alterations of cells that are directly and indirectly induced by multiple intrinsic (cellular) and extrinsic (micro-environmental) factors. To metastasize, a cancer cell often transitions from an epithelial to mesenchymal morphology (EMT), modifies the extracellular matrix, forms emboli and survives in the circulation, escapes immune surveillance, adheres to sites distant from the initial tumor and finally develops a blood supply (angiogenesis) and colonizes in a secondary niche (a micrometastasis). Scientific advances have greatly enhanced our understanding of the precise molecular and genetic changes, operating independently or collectively, that lead to metastasis. This review focuses on a unique gene, melanoma differentiation associated gene-9 (also known as Syntenin-1; Syndecan Binding Protein (sdcbp); mda-9/Syntenin), initially cloned and characterized from metastatic human melanoma and shown to be a pro-metastatic gene. In the last two decades, our comprehension of the diversity of actions of MDA-9/Syntenin on cellular phenotype has emerged. MDA-9/Sytenin plays pivotal regulatory roles in multiple signaling cascades and orchestrates both metastatic and non-metastatic events. Considering the relevance of this gene in controlling cancer invasion and metastasis, approaches have been developed to uniquely and selectively target this gene. We also provide recent updates on strategies that have been successfully employed in targeting MDA-9/Syntenin resulting in profound pre-clinical anti-cancer activity.

  • regulation of protective autophagy in anoikis resistant glioma stem cells by sdcbp mda 9 Syntenin
    Autophagy, 2018
    Co-Authors: Sarmistha Talukdar, Devanand Sarkar, Anjan K Pradhan, Praveen Bhoopathi, Xuening Shen, Jolene J Windle, Laura A August, Frank B Furnari, Webster K Cavenee, Swadesh K Das
    Abstract:

    Glioblastoma multiforme (GBM) is a frequent and aggressive glial tumor, containing a small population of therapy-resistant cells, glioma stem cells (GSCs). Current dogma suggests that tumors regrow from GSCs, and these cells contribute to therapy resistance, poor prognosis, and recurrence; highlighting the importance of GSCs in glioma pathophysiology and therapeutic targeting. Macroautophagy/autophagy-based cellular homeostasis can be changed from pro-survival to pro-cell death by modulating SDCBP/MDA-9/Syntenin (syndecan binding protein)-mediated signaling. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of SDCBP/MDA-9/Syntenin. Conversely, SDCBP/MDA-9/Syntenin silencing induces autophagic death in GSCs, indicating that SDCBP/MDA-9/Syntenin regulates protective autophagy in GSCs under anoikis conditions. This process is mediated through phosphorylation of the anti-apoptotic protein BCL2 accompanied with suppression of high levels of autophagic proteins (ATG5, LAMP1, LC3B) through EGFR signaling. SDCBP/MDA-9/Syntenin-mediated regulation of BCL2 and EGFR phosphorylation is achieved through PTK2/FAK and PRKC/PKC signaling. When SDCBP/MDA-9/Syntenin is absent, this protective mechanism is deregulated, leading to highly elevated and sustained levels of autophagy and consequently decreased cell survival. Our recent paper reveals a novel functional link between SDCBP/MDA-9/Syntenin expression and protective autophagy in GSCs. These new insights into SDCBP/MDA-9/Syntenin-mediated regulation and maintenance of GSCs present leads for developing innovative combinatorial cancer therapies.

  • the mda 9 Syntenin igf1r stat3 axis directs prostate cancer invasion
    Cancer Research, 2018
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xuening Shen, Paul B Fisher
    Abstract:

    Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [Syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/Syntenin-manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/Syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/Syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers.Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852-63. ©2018 AACR.

  • inhibition of radiation induced glioblastoma invasion by genetic and pharmacological targeting of mda 9 Syntenin
    Proceedings of the National Academy of Sciences of the United States of America, 2017
    Co-Authors: Timothy P Kegelman, Swadesh K Das, Devanand Sarkar, Luni Emdad, Kristoffer Valerie, Sarmistha Talukdar, Frank B Furnari, Webster K Cavenee, Jason M Beckta, Jun Wei
    Abstract:

    Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.

Swadesh K Das - One of the best experts on this subject based on the ideXlab platform.

  • suppression of prostate cancer pathogenesis using an mda 9 Syntenin sdcbp pdz1 small molecule inhibitor
    Molecular Cancer Therapeutics, 2019
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xuening Shen, Timothy P Kegelman, Santanu Maji, Paul B Fisher
    Abstract:

    Metastasis is the primary determinant of death in patients with diverse solid tumors and MDA-9/Syntenin (SDCBP), a pro-metastatic and pro-angiogenic gene, contributes to this process. Recently, we documented that by physically interacting with IGF-1R, MDA-9/Syntenin activates STAT3 and regulates prostate cancer pathogenesis. These observations firmly established MDA-9/Syntenin as a potential molecular target in prostate cancer. MDA-9/Syntenin contains two highly homologous PDZ domains predicted to interact with a plethora of proteins, many of which are central to the cancerous process. An MDA-9/Syntenin PDZ1 domain-targeted small molecule (PDZ1i) was previously developed using fragment-based drug discovery (FBDD) guided by NMR spectroscopy and was found to be well-tolerated in vivo, had significant half-life (t1/2 = 9 hours) and displayed substantial anti-prostate cancer preclinical in vivo activity. PDZ1i blocked tumor cell invasion and migration in vitro, and metastasis in vivo. Hence, we demonstrate that PDZ1i an MDA-9/Syntenin PDZ1 target-specific small-molecule inhibitor displays therapeutic potential for prostate and potentially other cancers expressing elevated levels of MDA-9/Syntenin.

  • mda 9 Syntenin an emerging global molecular target regulating cancer invasion and metastasis
    Advances in Cancer Research, 2019
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Paul B Fisher
    Abstract:

    With few exceptions, metastasis is the terminal stage of cancer with limited therapeutic options. Metastasis consists of numerous phenotypic and genotypic alterations of cells that are directly and indirectly induced by multiple intrinsic (cellular) and extrinsic (micro-environmental) factors. To metastasize, a cancer cell often transitions from an epithelial to mesenchymal morphology (EMT), modifies the extracellular matrix, forms emboli and survives in the circulation, escapes immune surveillance, adheres to sites distant from the initial tumor and finally develops a blood supply (angiogenesis) and colonizes in a secondary niche (a micrometastasis). Scientific advances have greatly enhanced our understanding of the precise molecular and genetic changes, operating independently or collectively, that lead to metastasis. This review focuses on a unique gene, melanoma differentiation associated gene-9 (also known as Syntenin-1; Syndecan Binding Protein (sdcbp); mda-9/Syntenin), initially cloned and characterized from metastatic human melanoma and shown to be a pro-metastatic gene. In the last two decades, our comprehension of the diversity of actions of MDA-9/Syntenin on cellular phenotype has emerged. MDA-9/Sytenin plays pivotal regulatory roles in multiple signaling cascades and orchestrates both metastatic and non-metastatic events. Considering the relevance of this gene in controlling cancer invasion and metastasis, approaches have been developed to uniquely and selectively target this gene. We also provide recent updates on strategies that have been successfully employed in targeting MDA-9/Syntenin resulting in profound pre-clinical anti-cancer activity.

  • regulation of protective autophagy in anoikis resistant glioma stem cells by sdcbp mda 9 Syntenin
    Autophagy, 2018
    Co-Authors: Sarmistha Talukdar, Devanand Sarkar, Anjan K Pradhan, Praveen Bhoopathi, Xuening Shen, Jolene J Windle, Laura A August, Frank B Furnari, Webster K Cavenee, Swadesh K Das
    Abstract:

    Glioblastoma multiforme (GBM) is a frequent and aggressive glial tumor, containing a small population of therapy-resistant cells, glioma stem cells (GSCs). Current dogma suggests that tumors regrow from GSCs, and these cells contribute to therapy resistance, poor prognosis, and recurrence; highlighting the importance of GSCs in glioma pathophysiology and therapeutic targeting. Macroautophagy/autophagy-based cellular homeostasis can be changed from pro-survival to pro-cell death by modulating SDCBP/MDA-9/Syntenin (syndecan binding protein)-mediated signaling. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of SDCBP/MDA-9/Syntenin. Conversely, SDCBP/MDA-9/Syntenin silencing induces autophagic death in GSCs, indicating that SDCBP/MDA-9/Syntenin regulates protective autophagy in GSCs under anoikis conditions. This process is mediated through phosphorylation of the anti-apoptotic protein BCL2 accompanied with suppression of high levels of autophagic proteins (ATG5, LAMP1, LC3B) through EGFR signaling. SDCBP/MDA-9/Syntenin-mediated regulation of BCL2 and EGFR phosphorylation is achieved through PTK2/FAK and PRKC/PKC signaling. When SDCBP/MDA-9/Syntenin is absent, this protective mechanism is deregulated, leading to highly elevated and sustained levels of autophagy and consequently decreased cell survival. Our recent paper reveals a novel functional link between SDCBP/MDA-9/Syntenin expression and protective autophagy in GSCs. These new insights into SDCBP/MDA-9/Syntenin-mediated regulation and maintenance of GSCs present leads for developing innovative combinatorial cancer therapies.

  • the mda 9 Syntenin igf1r stat3 axis directs prostate cancer invasion
    Cancer Research, 2018
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xuening Shen, Paul B Fisher
    Abstract:

    Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [Syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/Syntenin-manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/Syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/Syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers.Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852-63. ©2018 AACR.

  • inhibition of radiation induced glioblastoma invasion by genetic and pharmacological targeting of mda 9 Syntenin
    Proceedings of the National Academy of Sciences of the United States of America, 2017
    Co-Authors: Timothy P Kegelman, Swadesh K Das, Devanand Sarkar, Luni Emdad, Kristoffer Valerie, Sarmistha Talukdar, Frank B Furnari, Webster K Cavenee, Jason M Beckta, Jun Wei
    Abstract:

    Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.

Luni Emdad - One of the best experts on this subject based on the ideXlab platform.

  • suppression of prostate cancer pathogenesis using an mda 9 Syntenin sdcbp pdz1 small molecule inhibitor
    Molecular Cancer Therapeutics, 2019
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xuening Shen, Timothy P Kegelman, Santanu Maji, Paul B Fisher
    Abstract:

    Metastasis is the primary determinant of death in patients with diverse solid tumors and MDA-9/Syntenin (SDCBP), a pro-metastatic and pro-angiogenic gene, contributes to this process. Recently, we documented that by physically interacting with IGF-1R, MDA-9/Syntenin activates STAT3 and regulates prostate cancer pathogenesis. These observations firmly established MDA-9/Syntenin as a potential molecular target in prostate cancer. MDA-9/Syntenin contains two highly homologous PDZ domains predicted to interact with a plethora of proteins, many of which are central to the cancerous process. An MDA-9/Syntenin PDZ1 domain-targeted small molecule (PDZ1i) was previously developed using fragment-based drug discovery (FBDD) guided by NMR spectroscopy and was found to be well-tolerated in vivo, had significant half-life (t1/2 = 9 hours) and displayed substantial anti-prostate cancer preclinical in vivo activity. PDZ1i blocked tumor cell invasion and migration in vitro, and metastasis in vivo. Hence, we demonstrate that PDZ1i an MDA-9/Syntenin PDZ1 target-specific small-molecule inhibitor displays therapeutic potential for prostate and potentially other cancers expressing elevated levels of MDA-9/Syntenin.

  • mda 9 Syntenin an emerging global molecular target regulating cancer invasion and metastasis
    Advances in Cancer Research, 2019
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Paul B Fisher
    Abstract:

    With few exceptions, metastasis is the terminal stage of cancer with limited therapeutic options. Metastasis consists of numerous phenotypic and genotypic alterations of cells that are directly and indirectly induced by multiple intrinsic (cellular) and extrinsic (micro-environmental) factors. To metastasize, a cancer cell often transitions from an epithelial to mesenchymal morphology (EMT), modifies the extracellular matrix, forms emboli and survives in the circulation, escapes immune surveillance, adheres to sites distant from the initial tumor and finally develops a blood supply (angiogenesis) and colonizes in a secondary niche (a micrometastasis). Scientific advances have greatly enhanced our understanding of the precise molecular and genetic changes, operating independently or collectively, that lead to metastasis. This review focuses on a unique gene, melanoma differentiation associated gene-9 (also known as Syntenin-1; Syndecan Binding Protein (sdcbp); mda-9/Syntenin), initially cloned and characterized from metastatic human melanoma and shown to be a pro-metastatic gene. In the last two decades, our comprehension of the diversity of actions of MDA-9/Syntenin on cellular phenotype has emerged. MDA-9/Sytenin plays pivotal regulatory roles in multiple signaling cascades and orchestrates both metastatic and non-metastatic events. Considering the relevance of this gene in controlling cancer invasion and metastasis, approaches have been developed to uniquely and selectively target this gene. We also provide recent updates on strategies that have been successfully employed in targeting MDA-9/Syntenin resulting in profound pre-clinical anti-cancer activity.

  • the mda 9 Syntenin igf1r stat3 axis directs prostate cancer invasion
    Cancer Research, 2018
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xuening Shen, Paul B Fisher
    Abstract:

    Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [Syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/Syntenin-manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/Syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/Syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers.Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852-63. ©2018 AACR.

  • inhibition of radiation induced glioblastoma invasion by genetic and pharmacological targeting of mda 9 Syntenin
    Proceedings of the National Academy of Sciences of the United States of America, 2017
    Co-Authors: Timothy P Kegelman, Swadesh K Das, Devanand Sarkar, Luni Emdad, Kristoffer Valerie, Sarmistha Talukdar, Frank B Furnari, Webster K Cavenee, Jason M Beckta, Jun Wei
    Abstract:

    Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.

  • MDA-9/Syntenin is a key regulator of glioma pathogenesis
    2016
    Co-Authors: Timothy P Kegelman, Swadesh K Das, Luni Emdad, Mitchell E Menezes, Santanu Dasgupta, Albert S Baldwin, Manny D Bacolod, Christine E Fuller, Jeffery N Bruce
    Abstract:

    Background. The extraordinary invasiveness of human glioblastoma multiforme (GBM) contributes to treatment failure and the grim prognosis of patients diagnosed with this tumor. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene–9 (MDA-9/Syntenin) is a highly conserved PDZ domain–containing scaffolding protein that promotes invasion and metastasis in vitro and in vivo in human mel-anoma models. To determine whether MDA-9/Syntenin is a relevant target in GBM, we investigated its expression in tumor samples and involvement in GBM invasion and angiogenesis. Materials. We assessed MDA-9/Syntenin levels in available databases, patient tumor samples, and human-derived cell lines. Throug

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  • MDA-9/Syntenin is a key regulator of glioma pathogenesis
    2016
    Co-Authors: Timothy P Kegelman, Swadesh K Das, Luni Emdad, Mitchell E Menezes, Santanu Dasgupta, Albert S Baldwin, Manny D Bacolod, Christine E Fuller, Jeffery N Bruce
    Abstract:

    Background. The extraordinary invasiveness of human glioblastoma multiforme (GBM) contributes to treatment failure and the grim prognosis of patients diagnosed with this tumor. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene–9 (MDA-9/Syntenin) is a highly conserved PDZ domain–containing scaffolding protein that promotes invasion and metastasis in vitro and in vivo in human mel-anoma models. To determine whether MDA-9/Syntenin is a relevant target in GBM, we investigated its expression in tumor samples and involvement in GBM invasion and angiogenesis. Materials. We assessed MDA-9/Syntenin levels in available databases, patient tumor samples, and human-derived cell lines. Throug

  • mda 9 Syntenin control
    Journal of Cellular Physiology, 2016
    Co-Authors: Julie V Philley, Anbarasu Kannan, Santanu Dasgupta
    Abstract:

    MDA-9/Syntenin is a small PDZ domain containing scaffolding protein with diverse array of functions regulating membrane trafficking, cell adhesion, neural, and synaptic development, ubiquitination, and exosome biogenesis. An appreciable number of studies also established a pivotal role of MDA-9/Syntenin in cancer development and progression. In this review, we will discuss the dynamic role of MDA-9/Syntenin in regulating normal and abnormal fate of various cellular processes.

  • mda 9 Syntenin is a key regulator of glioma pathogenesis
    Neuro-oncology, 2014
    Co-Authors: Timothy P Kegelman, Swadesh K Das, Luni Emdad, Mitchell E Menezes, Santanu Dasgupta, Albert S Baldwin, Jeffery N Bruce, Manny D Bacolod, Christine E Fuller, Paul Dent
    Abstract:

    Background. The extraordinary invasiveness of human glioblastoma multiforme (GBM) contributes to treatment failure and the grim prognosis of patients diagnosed with this tumor. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene –9 (MDA-9/Syntenin) is a highly conserved PDZ domain –containing scaffolding protein that promotes invasion and metastasis in vitro and in vivo in human melanoma models. To determine whether MDA-9/Syntenin is a relevant target in GBM, we investigated its expression in tumor samples and involvement in GBM invasion and angiogenesis. Materials. We assessed MDA-9/Syntenin levels in available databases, patient tumor samples, and human-derived cell lines. Through gain-of-function and loss-of-function studies, we analyzed changes in invasion, angiogenesis, and signaling in vitro. We used orthotopic xenografts with GBM6 cells to demonstrate the role of MDA-9/Syntenin in GBM pathogenesis in vivo. Results. MDA-9/Syntenin expression in high-grade astrocytomas is significantly higher than normal tissue counterparts. Forced overexpression of MDA-9/Syntenin enhanced Matrigel invasion, while knockdown inhibited invasion, migration, and anchorage-independent growth in soft agar. Moreover, overexpression of MDA-9/Syntenin increased activation of c-Src, p38 mitogen-activated protein kinase, and nuclear factor kappa-B, leading to elevated expression of matrix metalloproteinase 2 and secretion of interleukin-8 with corresponding changes observed upon knockdown. GBM6 cells that stably express small hairpin RNA for MDA-9/Syntenin formed smaller tumors and had a less invasive phenotype in vivo. Conclusions. Our findings indicate that MDA-9/Syntenin is a novel and important mediator of invasion in GBM and a key regulator of pathogenesis, and we identify it as a potential target for anti-invasive treatment in human astrocytoma.

  • novel role of mda 9 Syntenin in regulating urothelial cell proliferation by modulating egfr signaling
    Clinical Cancer Research, 2013
    Co-Authors: Santanu Dasgupta, Swadesh K Das, Devanand Sarkar, Luni Emdad, Shilpa Bhatia, Mitchell E Menezes, Aleksandar Janjic, Nitai Mukhopadhyay, Chunbo Shao, Paul B Fisher
    Abstract:

    Purpose: Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression. Experimental Design: Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knockdown was examined in multiple cells lines and key findings were validated in primary tumors. Results: Significantly higher ( P = 0.002–0.003) expression of MDA-9/Syntenin was observed in 64% (28 of 44) of primary tumors and an association was evident with stage ( P = 0.01), grade ( P = 0.03), and invasion status ( P = 0.02). MDA-9/Syntenin overexpression in nontumorigenic HUC-1 cells increased proliferation ( P = 0.0012), invasion ( P = 0.0001), and EGF receptor (EGFR), AKT, phosphoinositide 3-kinase (PI3K), and c-Src expression. Alteration of β-catenin, E-cadherin, vimentin, claudin-1, ZO-1, and T-cell factor-4 (TCF4) expression was also observed. MDA-9/Syntenin knockdown in three UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and colocalization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin:AKT expressions with stage ( P = 0.04, EGFR; P = 0.01, AKT). A correlation between MDA-9/Syntenin:β-catenin coexpression with stage ( P = 0.03) and invasion ( P = 0.04) was also evident. Conclusions: Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring, and therapeutic strategies for managing UCC. Clin Cancer Res; 19(17); 4621–33. ©2013 AACR .

  • abstract 3902 mda 9 Syntenin and igfbp 2 promote angiogenesis in human melanoma
    Cancer Research, 2013
    Co-Authors: Swadesh K Das, Devanand Sarkar, Luni Emdad, Paul B Fisher, Timothy P Kegelman, Prasanna K Santhekadur, Santanu Dasgupta, Paul Dent, Steven Grant, Maurizio Pellecchia
    Abstract:

    Vascularization of tumors promotes not only their survival and growth, but also facilitates metastases from primary to distant sites. For that reason, understanding the molecular determinants controlling tumor angiogenesis is mandatory to develop clinically efficacious angiogenesis inhibitors for cancer therapy. Melanoma differentiation associated gene or mda-9, also known as Syntenin, is a multifunctional scaffold protein that cross talks with a plethora of proteins and regulates diverse physiological and pathological processes, including tumor progression and metastasis. Since, tumor angiogenesis promotes metastasis, we hypothesized that in addition to augmenting invasion and migration, MDA-9/Syntenin might also promote angiogenesis thereby facilitating tumor progression and metastasis. Genetic (gain-of-function and loss-of-function) and pharmacological approaches were employed to modify mda-9/Syntenin expression in normal immortal melanocytes, early radial growth phase melanoma and metastatic melanoma cells. The consequence of modifying mda-9/Syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chicken choriallantoic membrane assays (CAM assays) and xenograft tumor animal models. Employing both genetic and chemical approaches we now demonstrate that MDA-9/Syntenin expression correlates with in vitro and in vivo (tumorigenic/metastatic) transformed/invasive phenotypes of human melanoma. Additionally, our immunohistochemical and in vivo CAM assays confirm that angiogenesis is an essential component of MDA-9/Syntenin-induced tumor progression. To define how MDA-9/Syntenin regulates angiogenesis we identified and analyzed several potential downstream gene targets of MDA-9/Syntenin. One gene implicated in induction of vasculogenesis is insulin growth factor binding protein-2 (IGFBP-2), which is transcriptionally regulated by hypoxia inducible factor-1 as a consequence of MDA-9/Syntenin and Src interaction. IGFBP-2 transcriptionally regulates VEGF-A in an AKT-dependent manner through interaction with V 3 integrin resulting in angiogenesis. Our studies delineate an unanticipated cell non-autonomous function of MDA-9/Syntenin in the context of angiogenesis by augmenting expression of several pro-angiogenic factors including IGFBP-2, which may provide a complementary way to promote metastasis. As a result, targeting MDA-9/Syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (non-autonomous). Citation Format: Swadesh K. Das, Timothy P. Kegelman, Prasanna K. Santhekadur, Santanu Dasgupta, Paul Dent, Steven Grant, Luni Emdad, Devanand Sarkar, Paul B. Fisher, Maurizio Pellecchia. MDA-9/Syntenin and IGFBP-2 promote angiogenesis in human melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3902. doi:10.1158/1538-7445.AM2013-3902

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