1. Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β.
- Author
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Pradhan AK, Maji S, Bhoopathi P, Talukdar S, Mannangatti P, Guo C, Wang XY, Cartagena LC, Idowu M, Landry JW, Sarkar D, Emdad L, Cavenee WK, Das SK, and Fisher PB
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, 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 immunology, Interleukin-23 Subunit p19 genetics, Interleukin-23 Subunit p19 immunology, Interleukin-5 genetics, Interleukin-5 immunology, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms secondary, Mice, Mice, Inbred BALB C, Oxadiazoles chemical synthesis, Pyrimidines chemical synthesis, Signal Transduction, Syntenins antagonists & inhibitors, Syntenins immunology, T-Lymphocytes, Cytotoxic drug effects, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic pathology, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Interleukin-1beta genetics, Lung Neoplasms drug therapy, Oxadiazoles pharmacology, Pyrimidines pharmacology, Syntenins genetics
- 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., Competing Interests: Competing interest statement: W.K.C. and P.B.F. are cofounders and have ownership interest in InVaMet Therapeutics, Inc. Virginia Commonwealth University and the Sanford Burnham Prebys Medical Discovery Institute have ownership interest in InVaMet Therapeutics, Inc.
- Published
- 2021
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