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