Lichen-Derived Depsides and Depsidones Modulate the Nrf2, NF-κB and STAT3 Signaling Pathways in Colorectal Cancer Cells.

Katarzyna Papierska,Violetta Krajka-Kuźniak,Wanda Baer-Dubowska,Marcin Skalski,Jarosław Paluszczak,Elżbieta Studzińska-Sroka,Robert Kleszcz

doi:10.3390/molecules26164787

Katarzyna Papierska, Violetta Krajka-Kuźniak + Show 5 more

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https://doi.org/10.3390/molecules26164787

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Abstract

The study aimed to evaluate the possible modulation of Nrf2, NF-ĸB and STAT3 signaling pathways in the colorectal cancer (CRC) cells line DLD-1 and HCT116 by secondary metabolites of lichens. An attempt was made to indicate the most promising targets in these signaling pathways. Attention was also paid to the effects of the compounds tested on CRC cells using anakoinosis—that is, simultaneous analysis of several signaling pathways. The effects of the tested natural compounds on the activity of selected transcriptional factors related to CRC were analyzed by Western blot and RT-PCR assays. The highest activity against CRC cells was shown by physodic and salazinic acids from the studied secondary metabolites of lichens. As a result, an increase in the activation of transcription factor Nrf2 and the expression of its selected target genes was observed. Physodic and salazinic acids induced the opposite effect in relation to the NF-κB and STAT3 pathways. These results confirmed our earlier observations that lichen-derived compounds have the ability to modulate signaling pathway networks. While caperatic acid affected Wnt/β-catenin to the most extent, salazinic acid was the most potent modulator of Nrf2, NF-κB and STAT3 pathways. Physodic acid seemed to affect all the investigated pathways.

Highlights

Lichens are the symbionts of nutritionally specialized fungi that derive fixed carbon from algae and/or cyanobacteria and are present in ecosystems worldwide [1]
Lichens are a known source of unique secondary metabolites, many of which play important ecological roles, including regulating the equilibrium between symbionts
The interconnection of signaling pathways such as Wnt/β-catenin, Nrf2-ARE, NF-κB and STAT3 and their aberrations lead to disturbance of cell homeostasis and are the main causative factors involved in the development of colorectal cancer cells

Summary

Introduction

Lichens are the symbionts of nutritionally specialized fungi (mycobiont) that derive fixed carbon from algae and/or cyanobacteria (photobionts) and are present in ecosystems worldwide [1]. Secondary metabolites present in lichens comprise aliphatic, cycloaliphatic, aromatic and terpenic compounds, which are unique with respect to those of higher plants and show interesting biological and pharmacological activities [3]. Only a few of these compounds have been assessed for their potential chemopreventive and/or therapeutic activities toward cancer. In this regard, a depside, atranorin, and a depsidone, physodic acid, both synthesized by lichens in the acetyl-polymalonyl pathways, have been shown to display cytotoxic effects in breast [4] and melanoma cancer cells [3], activating an apoptotic process in the latter cells. It was suggested that atranorin may act as a pro-oxidant or antioxidant agent depending on the radical [5]

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