A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion

PloS One
Magdalena L CircuHazem El-Osta

Abstract

Lysosome trafficking plays a significant role in tumor invasion, a key event for the development of metastasis. Previous studies from our laboratory have demonstrated that the anterograde (outward) movement of lysosomes to the cell surface in response to certain tumor microenvironment stimulus, such as hepatocyte growth factor (HGF) or acidic extracellular pH (pHe), increases cathepsin B secretion and tumor cell invasion. Anterograde lysosome trafficking depends on sodium-proton exchanger activity and can be reversed by blocking these ion pumps with Troglitazone or EIPA. Since these drugs cannot be advanced into the clinic due to toxicity, we have designed a high-content assay to discover drugs that block peripheral lysosome trafficking with the goal of identifying novel drugs that inhibit tumor cell invasion. An automated high-content imaging system (Cellomics) was used to measure the position of lysosomes relative to the nucleus. Among a total of 2210 repurposed and natural product drugs screened, 18 "hits" were identified. One of the compounds identified as an anterograde lysosome trafficking inhibitor was niclosamide, a marketed human anti-helminthic drug. Further studies revealed that niclosamide blocked acidic pHe, HGF, a...Continue Reading

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Citations

Dec 18, 2019·Journal of Cellular Physiology·Sowjanya ThatikondaChandraiah Godugu
Nov 2, 2016·Journal of Cell Science·Jing PuJuan S Bonifacino
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Mar 13, 2019·Chinese Medicine·Jing WangJia-Hong Lu

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Methods Mentioned

BETA
GTPases
GTPase
fluorescence microscopy
fluorescence
transfection
dissection

Software Mentioned

Leica LAS AF
GraphPad Prism
Cellomics
Microsoft excel
LAS AF
Cellomics Imager
IncuCyte
IncuCyte Imager
Cellomics analysis
MetaMorph

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