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Peptides derived from the extracellular domain of the somatostatin receptor splicing variant SST5TMD4 increase malignancy in multiple cancer cell types

  • Mercedes del Rio-Moreno
    Affiliations
    Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain

    Universidad de Córdoba, Córdoba, Spain

    Reina Sofia University Hospital, Córdoba, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain

    Agrifood Campus of International Excellence (ceiA3), Córdoba, Spain
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  • Emilia Alors-Perez
    Affiliations
    Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain

    Universidad de Córdoba, Córdoba, Spain

    Reina Sofia University Hospital, Córdoba, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain

    Agrifood Campus of International Excellence (ceiA3), Córdoba, Spain
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  • Patricia Borges de Souza
    Affiliations
    Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain

    Universidad de Córdoba, Córdoba, Spain

    Reina Sofia University Hospital, Córdoba, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain

    Agrifood Campus of International Excellence (ceiA3), Córdoba, Spain
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  • Maria E. Prados-Gonzalez
    Affiliations
    Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain

    Universidad de Córdoba, Córdoba, Spain

    Reina Sofia University Hospital, Córdoba, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain

    Agrifood Campus of International Excellence (ceiA3), Córdoba, Spain
    Search for articles by this author
  • Justo P. CastaÑo
    Correspondence
    Reprint requests: Manuel D. Gahete, Raúl M. Luque and Justo P. Castaño. Edificio IMIBIC. Av. Menéndez Pidal s/n, Córdoba 14004, Spain.
    Affiliations
    Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain

    Universidad de Córdoba, Córdoba, Spain

    Reina Sofia University Hospital, Córdoba, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain

    Agrifood Campus of International Excellence (ceiA3), Córdoba, Spain
    Search for articles by this author
  • Raul M. Luque
    Correspondence
    Reprint requests: Manuel D. Gahete, Raúl M. Luque and Justo P. Castaño. Edificio IMIBIC. Av. Menéndez Pidal s/n, Córdoba 14004, Spain.
    Affiliations
    Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain

    Universidad de Córdoba, Córdoba, Spain

    Reina Sofia University Hospital, Córdoba, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain

    Agrifood Campus of International Excellence (ceiA3), Córdoba, Spain
    Search for articles by this author
  • Manuel D. Gahete
    Correspondence
    Reprint requests: Manuel D. Gahete, Raúl M. Luque and Justo P. Castaño. Edificio IMIBIC. Av. Menéndez Pidal s/n, Córdoba 14004, Spain.
    Affiliations
    Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain

    Universidad de Córdoba, Córdoba, Spain

    Reina Sofia University Hospital, Córdoba, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain

    Agrifood Campus of International Excellence (ceiA3), Córdoba, Spain
    Search for articles by this author
Published:March 02, 2019DOI:https://doi.org/10.1016/j.trsl.2019.02.013
      Extracellular fragments derived from plasma membrane receptors can play relevant roles in the development/progression of tumor pathologies, thereby offering novel diagnostic or therapeutic opportunities. The truncated variant of somatostatin receptor subtype-5, SST5TMD4, is an aberrantly spliced receptor with 4 transmembrane domains, highly overexpressed in several tumor types, whose C-terminal tail is exposed towards the extracellular matrix, and could therefore be the substrate for proteolytic enzymes. In silico analysis implemented herein predicted 2 possible cleavage sites for metalloproteases MMP2, 9, 14, and 16 in its sequence, which could generate 3 releasable peptides. Of note, expression of those MMPs was directly correlated with SST5TMD4 in several cancer-derived cell lines (ie neuroendocrine tumors and prostate, breast, and liver cancers). Moreover, incubation with SST5TMD4-derived peptides enhanced malignancy features in all cancer cell types tested (ie proliferation, migration, etc.) and blunted the antiproliferative response to somatostatin in QGP-1 cells, acting probably through PI3K/AKT and/or MEK/ERK signaling pathways and the modulation of key cancer-associated genes (eg MMPs, MKI67, ACTR2/3, CD24/44). These results suggest that SST5TMD4-derived peptides could contribute to the strong oncogenic role of SST5TMD4 observed in multiple tumor pathologies, and, therefore, represent potential candidates to identify novel diagnostic, prognostic, or therapeutic targets in cancer.

      Abbreviations:

      CSCs (cancer stem cells), ECM (extracellular matrix), GPCR (G-protein coupled receptor), HCC (hepatocellular carcinoma), IGF1 (insulin-like growth factor 1), MMP (matrix metalloproteinase), NET (neuroendocrine tumor), SS14 (somatostatin 14), SSA (somatostatin analog), SST1-5 (somatostatin receptors 1-5), SST5TMD4 (somatostatin receptor 5 variant with 4 transmembrane domains), TMD (transmembrane domain)
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