Proton-Shuttling Lichen Compound Usnic Acid Affects Mitochondrial and Lysosomal Function in Cancer Cells

Margret Bessadottir,Margret H Ogmundsdottir,Sesselja Omarsdottir,Iris H Magnusdottir,Eydis Einarsdottir,Helga M Ogmundsdottir,Mar Egilsson,Gabriele Multhoff

doi:10.1371/journal.pone.0051296

Abstract

The lichen compound usnic acid (UA) is a lipophilic weak acid that acts as a proton shuttle and causes loss of mitochondrial inner membrane potential. In the current study we show that UA treatment induced the formation of autophagosomes in human cancer cells, but had minimal effects on normal human fibroblasts. However, autophagic flux was incomplete, degradation of autophagosomal content did not occur and acidification was defective. UA-treated cells showed reduced ATP levels and activation of AMP kinase as well as signs of cellular stress. UA is thus likely to trigger autophagosome formation both by energy depletion and stress conditions. Our findings indicate that the H+-shuttling effect of UA operates not only in mitochondria as previously shown, but also in lysosomes, and have implications for therapeutic manipulation of autophagy and pH-determined drug distribution.

Highlights

Lichens, the symbiosis between a fungal partner and a photobiotic microorganism, are found all around the world and give rise to a large number of unique secondary metabolites [1]
It has been shown that usnic acid has anti-mitotic effects on human cancer cell lines [5] and causes a loss of viable cells in leukemia, lung and breast cancer cells [6,7]
The intrinsic pathway of apoptosis is triggered by opening of pores into the outer mitochondrial membrane leading to release of cytochrome c into the cytosol and activation of the caspase cascade

Summary

Introduction

The symbiosis between a fungal partner and a photobiotic microorganism, are found all around the world and give rise to a large number of unique secondary metabolites [1]. Our previous study showed that UA treatment causes loss of mitochondrial membrane potential in two different cancer cell lines [12]. To follow up on our previous work on the effects of UA on mitochondrial membrane potential [12] we investigated cytochrome c leakage and cleavage of caspase-3 by immunostaining in the breast cancer cell line T47D and the pancreatic cell line Capan2.

Results

Conclusion