HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers

Abstract

SummaryHepatocyte 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 epithelialmesenchymal 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 HGFoverexpressing 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.

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

“…These effects suggest that lysosome transport is required to maintain the structure and function of growth cones. Lysosomes could deliver adhesion or signaling molecules to the growth cone, as they do to focal adhesions in nonpolarized cells (61)(62)(63). This explanation is consistent with the requirement of lysosome exocytosis for the extension and arborization of neurites in sympathetic neurons (29).…”

Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production

“…Moreover, cathepsins released from cancer cells participate in the degradation of the extracellular matrix to promote tumor cell migration and angiogenesis (67). Clustering of lysosomes can limit invasiveness (68) and may be a possible mechanism by which ART reduces cell migration and invasion (69). Similarly, clustering of Rab5-labeled vesicles, which participate in both autophagy (70) and endocytosis (70), may alter the endocytotic capacity of the cell.…”

The PCa Tumor Microenvironment

“…It promotes scatter through downregulation of E-cadherin [102]. Invasion is mediated by HGF through HGF-induced anterograde lysosome trafficking that is dependent upon the PI3K pathway, microtubules and RhoA, resulting in increased cathepsin B secretion and invasion by the cells [103]. In addition to direct cancer effect, HGF may impact the bone microenvironment through induction of osteoblastic proteins in PCa as HGF upregulates bone morphogenetic protein receptor expression [104] and BMP-7 expression in PCa cells.…”