The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis

Abstract

Lichens are symbiotic organisms that produce various secondary metabolites. Here, different lichen extracts were examined to identify secondary metabolites with anti-migratory activity against human lung cancer cells. Everniastrum vexans had the most potent inhibitory activity, and atranorin was identified as an active subcomponent of this extract. Atranorin suppressed 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, cyclin-D1 and c-myc. Atranorin decreased KAI1 C-terminal interacting tetraspanin (KITENIN)-mediated AP-1 activity and the activity of the KITENIN 3′-untranslated region. The nuclear distribution of the AP-1 transcriptional factor, including c-jun and c-fos, was suppressed in atranorin-treated cells, and atranorin inhibited the activity of Rho GTPases including Rac1, Cdc42, and RhoA, whereas it had no effect on epithelial-mesenchymal transition markers. STAT-luciferase activity and nuclear STAT levels were decreased, whereas total STAT levels were moderately reduced. The human cell motility and lung cancer RT² Profiler PCR Arrays identified additional atranorin target genes. Atranorin significantly inhibited tumorigenesis in vitro and in vivo. Taken together, our results indicated that E. vexans and its subcomponent atranorin may inhibit lung cancer cell motility and tumorigenesis by affecting AP-1, Wnt, and STAT signaling and suppressing RhoGTPase activity.

Anticancer Potential of Lichens’ Secondary Metabolites

“…In another study, ATR reduced tumor volume and weight and diminished Ki-67 marker of proliferation in Lewis lung carcinoma xenograft model in C57BL/6 mice. Moreover, ATR decreased the expression of KITENIN, CD44, STAT, and cyclin-D1 genes in both in vitro as well as in in vivo conditions [20].…”

“…Moreover, ATR decreased the mRNA expression of KITENIN and increased the expression of KAI1 mRNA. It also decreased the level of GTP-Cdc42, GTP-RhoA and STAT proteins [20].…”

“…Interestingly, anticancer potential of lichens can also be maintained by modulation of pathways associated with the cancer invasiveness such as c-Met, which acts as mesenchymal epithelial transition factor regulating PI3K/Akt/mTOR, Paxillin/Rac-1, and STATs signaling cascades [33]. Despite regulation of STAT3 activity, [20,34] lichens target β-catenin or its downstream effectors that consequently lead to the modulation of Wnt/β-catenin target genes including the cell cycle regulating genes (c-myc, cyclin D1) as well as genes associated with cell migration (MMP7), apoptosis (BIRC5) or other regulators such as Axin2 [20,26]. Additionally, regulation of c-Jun and c-fos, members of the AP-1 family of critical regulators of gene expression and reduction of KITENIN-mediated AP-1 activity are also associated with anticancer mechanisms of lichens [20].…”

“…Secondary metabolites present in lichens include aliphatic, cycloaliphatic, aromatic, and terpenic compounds, which demonstrate significant biological and pharmacological effects including those of anti-inflammatory, antiviral, antibacterial, analgesic, antipyretic, anti-proliferative, and cytotoxic [17]. These compounds have demonstrated also antineoplastic activities in preclinical research in which revealed significant effects against cancer cells [18][19][20][21][22].…”

Therapeutic Effects of Atranorin towards the Proliferation of Babesia and Theileria Parasites

“…It was first isolated by Hesse in 1898 and since then its pharmacological and biological properties have been extensively examined and evaluated [6]. Notably, previous studies documented its in vitro as well as in vivo activities as an anti-inflammatory, antioxidant, analgesic, immunomodulatory, anticancer, antiprotozoal, antiviral, antifungal, and antibacterial agent against Gram-negative bacteria [7][8][9][10]. Ranković et al [11] documented the potent antibacterial activity of ATR against the most dangerous respiratory tract bacteria, Staphylococcus aureus, comparable to streptomycin.…”