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

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.

In Vitro and in Silico Studies of Lichen Compounds Atranorin and Salazinic Acid as Potential Antioxidant, Antibacterial and Anticancer Agents

“…It was suggested that it might suppress RhoGTPase activity and influence AP‐1, Wnt, and STAT signalling to inhibit lung cancer cell motility and carcinogenesis [32] . A recent study has shown that salazinic acid modulates the Nrf2, NF‐κB, and STAT3 pathways in colorectal cancer [33] …”

“…[32] A recent study has shown that salazinic acid modulates the Nrf2, NF-kB, and STAT3 pathways in colorectal cancer. [33] This is the first study in which Molecular docking experiments were carried out to determine the binding orientation of atranorin and salazinic acid to ERα, EGFR, mTOR, and PgR to estimate the stable binding conformation and binding affinity of the lichen compounds with proteins. Among the two lichen metabolites screened, atranorin exhibited docking energy values above À 5 Kcal/mol for receptor ERα, mTOR, and PgR.…”

Lichen Secondary Metabolites Inhibit the Wnt/β-Catenin Pathway in Glioblastoma Cells and Improve the Anticancer Effects of Temozolomide

“…Our previous studies revealed that lichen secondary metabolites, especially caperatic acid and physodic acid, exert anticancer properties, inhibiting Wnt/β-catenin pathway in colorectal cancer cells [ 15 , 37 ]. Moreover, in a study by Zhou et al, atranorin was found to suppress β-catenin-mediated TOPFLASH activity by inhibiting the nuclear import of β-catenin and downregulating β-catenin/LEF and c-jun/AP-1 downstream target genes such as CD44 , CCND1 , and c-MYC in lung cancer cells [ 32 ].…”

5-Fluorouracil Combined with Rutaecarpine Synergistically Suppresses the Growth of Colon Cancer Cells by Inhibiting STAT3

“… 21 Although the STAT3 pathway is regulated by various signaling mechanisms, STAT3 is stimulated by a variety of stimuli, including stress and cytokines. 22 Communication between cancer and inflammatory cells is highly dependent on STAT3 activation and interaction. 23 …”