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A novel drug inhibits exosome content loading and secretion in ovarian cancer cells
Author(s) -
Vaughn Kiera,
Lausen James,
Bruns Matthew,
Benbrook Doris,
Hannafon Bethany
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04409
Subject(s) - exosome , microvesicles , secretion , microbiology and biotechnology , tumor microenvironment , ovarian cancer , extracellular vesicle , cancer cell , biology , cancer research , microrna , chemistry , cancer , biochemistry , genetics , tumor cells , gene
Ovarian cancer is the 5 th leading cause of cancer deaths in women due to late stage diagnosis and limited treatment options. Exosomes are nanometer‐sized vesicles produced in multi‐vesicular bodies (MVBs) and released into the extracellular environment. Exosomes play a role in the progression of ovarian cancer by encapsulating and transferring DNA, RNA (including microRNAs), proteins, and lipids between cells and modifying the tumor microenvironment. Data from our laboratory shows that a novel drug binds to proteins involved in exosome secretion, transport, and content loading, including microRNA binding proteins. The goal of this research is to determine whether this novel drug, called tumor exosome inhibitor (TEXi), can prevent secretion and/or content loading of ovarian cancer exosomes. Using an exosome secretion assay (CD63‐nanoluciferase), nanoparticle tracking analysis, and western blot we found that TEXi inhibits exosome secretion in ovarian cancer cells. Ovarian cancer cells expressing CD63 tagged with GFP allowed for visualization of exosome production and co‐staining for lysosomes and mitochondria allowed for the visualization of the relationship between exosome production in MVBs and these other organelles. Treatment with TEXi followed by live and fixed‐cell imaging demonstrated that TEXi inhibits the secretion by promoting fusion of MVBs with the lysosome. Exosome microRNA secretion, measured by qRT‐PCR, was also reduced by TEXi treatment. In conclusion, TEXi can block exosome and microRNA release by promoting MVB lysosomal degradation. This study has identified a potential new strategy for the treatment of ovarian cancer by blocking the effect of exosomes on the tumor microenvironment. Support or Funding Information Native American Research Center for Health (NARCH), American Society of Investigative Pathology‐Summer Research Opportunity Program in Pathology (ASIP‐SROPP) and Oklahoma Center for the Advancement of Science and Technology (OCAST) HR17‐052 .