Effects of Na+/H+ exchanger inhibitors on subcellular localisation of endocytic organelles and intracellular dynamics of protein transduction domains HIV–TAT peptide and octaarginine

Fretz, Marjan M.; Jin, Jing; Conibere, Robin John; Penning, Neal Aart; Al-Taei, Saly; Storm, Gert; Futaki, Shiroh; Takeuchi, Toshihide; Nakase, Ikuhiko; Jones, Arwyn Tomos

doi:10.1016/j.jconrel.2006.07.009

Cited by 87 publications

(90 citation statements)

References 34 publications

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“…7B). In fact, perinuclear located LAMP-1-positive vesicles were enlarged in cells treated with EIPA as previously described (Fretz et al, 2006), which we suggest may be due to the increase in lysosomal membrane cholesterol. Thus, it appears that although these two compounds (Troglitazone and EIPA) inhibit NHEs, induce retrograde lysosome trafficking, and prevent cathepsin B secretion and invasion, they may act by different mechanisms.…”

Section: Discussionsupporting

confidence: 86%

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

Steffan

Williams

Welbourne

et al. 2010

Journal of Cell Science

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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.

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Section: Discussionsupporting

confidence: 86%

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

Steffan

Williams

Welbourne

et al. 2010

Journal of Cell Science

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“…13,23,35) Co-incubation of R8 together with propidium iodide (PI), a nuclear probe that is impermeable to intact membranes, resulted in no apparent staining of PI in cell nucleus, suggesting that cytosolic distribution of R8 is not attributed by significant membrane disruption as occurs in methanol-fixed cells. Likewise, similar cytosolic distribution of Tat and R8 is observed in living unfixed cells, when cells are treated with the pharmacological inhibitors for endocytosis such as 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) 36) and methyl-β-cyclodextrin. 37) These results collectively indicate that an endocytosis-independent pathway that enables direct translocation across membranes would be involved in internalization of these peptides.…”

Section: Direct Penetration Of Arginine-rich Cpps Into Cellsmentioning

confidence: 64%

Current Understanding of Direct Translocation of Arginine-Rich Cell-Penetrating Peptides and Its Internalization Mechanisms

2016

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Arginine-rich cell-penetrating peptides (CPPs) including Tat, Penetratin and oligoarginine peptides are a series of short peptides that can be efficiently internalized into cells and have been widely used as carriers for intracellular delivery of bioactive molecules. In the early phase of the study, CPPs, as well as their conjugates, were thought to rapidly enter cells by direct penetration through membranes, which was later found to be an experimental artifact that was concluded from observations in fixed cells. Although re-evaluation using living unfixed cells revealed that endocytosis has a major role in internalization of these peptides, there are a number of studies reporting that, even if fixation is avoided, direct translocation across plasma membranes and cytosolic distribution of arginine-rich CPPs are still observed in cells without membrane perturbation. In addition, amphiphilic counteranions such as pyrenebutyrate dramatically accelerate direct translocation of these peptides into cells. These results suggest that there are at least two pathways, i.e., endocytosis and direct translocation, both of which would contribute to cellular internalization of arginine-rich CPPs. In this review, we first introduce the story of fixation artifact, which indeed led to the critical progress in CPP study, and then summarize the current understanding for direct translocation of arginine-rich CPPs. Comprehensive understanding of direct translocation of these peptides and its mechanistic elucidation would provide useful knowledge for developing methodologies that would enable efficient intracellular delivery.

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“…1C and D), yet the percentage of EHV-4-infected cells was slightly reduced in the presence of EIPA. Although this reduction was not significant (P Ͼ 0.05), it may reflect interference of the drug with another endocytic pathway, as EIPA has been shown to have pleiotropic effects on other endocytic processes (42). In addition, incubation of CHO-K1 or Vero cells with chlorpromazine did not inhibit infection with either EHV-1 or EHV-4, respectively (data not shown).…”

Section: Resultsmentioning

confidence: 91%

Glycoprotein H and α4β1 Integrins Determine the Entry Pathway of Alphaherpesviruses

Azab

Lehmann

Osterrieder

2013

J Virol

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c Herpesviruses enter cells either by direct fusion at the plasma membrane or from within endosomes, depending on the cell type and receptor(s). We investigated two closely related herpesviruses of horses, equine herpesvirus type 1 (EHV-1) and EHV-4, for which the cellular and viral determinants routing virus entry are unknown. We show that EHV-1 enters equine epithelial cells via direct fusion at the plasma membrane, while EHV-4 does so via an endocytic pathway, which is dependent on dynamin II, cholesterol, caveolin 1, and tyrosine kinase activity. Exchange of glycoprotein H (gH) between EHV-1 and EHV-4 resulted in rerouting of EHV-1 to the endocytic pathway, as did blocking of ␣4␤1 integrins on the cell surface. Furthermore, a point mutation in the SDI integrin-binding motif of EHV-1 gH also directed EHV-1 to the endocytic pathway. Cumulatively, we show that viral gH and cellular ␣4␤1 integrins are important determinants in the choice of alphaherpesvirus cellular entry pathways.

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Effects of Na+/H+ exchanger inhibitors on subcellular localisation of endocytic organelles and intracellular dynamics of protein transduction domains HIV–TAT peptide and octaarginine

Cited by 87 publications

References 34 publications

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

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

Current Understanding of Direct Translocation of Arginine-Rich Cell-Penetrating Peptides and Its Internalization Mechanisms

Glycoprotein H and α4β1 Integrins Determine the Entry Pathway of Alphaherpesviruses

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