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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Chemokine CCL11 / genetics
  • Chemokine CCL11 / immunology
  • Chemokine CCL17 / genetics
  • Chemokine CCL17 / immunology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Interleukin-1alpha / genetics
  • Interleukin-1alpha / immunology
  • Interleukin-1beta / antagonists & inhibitors
  • Interleukin-1beta / genetics*
  • Interleukin-1beta / immunology
  • Interleukin-23 Subunit p19 / genetics
  • Interleukin-23 Subunit p19 / immunology
  • Interleukin-5 / genetics
  • Interleukin-5 / immunology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred BALB C
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Signal Transduction
  • Syntenins / antagonists & inhibitors
  • Syntenins / genetics*
  • Syntenins / immunology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / pathology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • CCL11 protein, human
  • CCL17 protein, human
  • Chemokine CCL11
  • Chemokine CCL17
  • IL10 protein, human
  • IL1A protein, human
  • IL1B protein, human
  • IL23A protein, human
  • IL5 protein, human
  • Interleukin-1alpha
  • Interleukin-1beta
  • Interleukin-23 Subunit p19
  • Interleukin-5
  • Oxadiazoles
  • Pyrimidines
  • SDCBP protein, human
  • Syntenins
  • Interleukin-10