2. Academic Validation
  3. Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β

Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β

  • Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2103180118. doi: 10.1073/pnas.2103180118.
Anjan K Pradhan 1 2,  Santanu Maji 1,  Praveen Bhoopathi 1 2,  Sarmistha Talukdar 1 2,  Padmanabhan Mannangatti 1,  Chunqing Guo 1 3,  Xiang-Yang Wang 1 2 3,  Lorraine Colon Cartagena 3 4,  Michael Idowu 3 4,  Joseph W Landry 1 2 3,  Devanand Sarkar 1 2 3,  Luni Emdad 1 2 3,  Webster K Cavenee 5,  Swadesh K Das 6 2 3,  Paul B Fisher 6 2 3
Affiliations

Affiliations

  • 1 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
  • 2 Virginia Commonwealth University Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
  • 3 Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
  • 4 Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
  • 5 Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093 wcavenee@ucsd.edu Swadesh.Das@vcuhealth.org paul.fisher@vcuhealth.org.
  • 6 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298; wcavenee@ucsd.edu Swadesh.Das@vcuhealth.org paul.fisher@vcuhealth.org.
PMID: 34016751 DOI: 10.1073/pnas.2103180118
Abstract

Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse Cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in Cancer. Knockdown of MDA-9/Syntenin decreases Cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill Cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1β pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive Cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast Cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast Cancer pathogenesis.

Keywords

IL-1β; MDA-9/Syntenin; breast cancer; metastasis.

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