Hepatocyte growth factor (HGF) is found in tumor microenvironments, and interaction with its
tyrosine kinase receptor Met triggers cell invasion and
metastasis. It was previously shown that acidic extracellular pH stimulated peripheral lysosome trafficking, resulting in increased
cathepsin B secretion and
tumor cell invasion, which was dependent upon
sodium-
proton exchanger (NHE) activity. We now demonstrate that HGF induced the trafficking of lysosomes to the cell periphery, independent of HGF-induced epithelial-mesenchymal transition. HGF-induced anterograde lysosome trafficking depended upon the PI3K pathway, microtubules and RhoA, resulting in increased
cathepsin B secretion and invasion by the cells. HGF-induced NHE activity via increased net
acid production, and inhibition of NHE activity with 5-(N-ethyl-N-isopropyl)-amiloride (
EIPA), or a combination of the NHE1-specific
drug cariporide and the NHE3-specific
drug s3226 prevented HGF-induced anterograde trafficking and induced retrograde trafficking in HGF-overexpressing cells.
EIPA treatment reduced
cathepsin B secretion and HGF-induced invasion by the
tumor cells. Lysosomes were located more peripherally in Rab7-shRNA-expressing cells and these cells were more invasive than control cells. Overexpression of the Rab7 effector
protein, RILP, resulted in a juxtanuclear location of lysosomes and reduced HGF-induced invasion. Together, these results suggest that the location of lysosomes is an inherently important aspect of invasion by
tumor cells.