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Colorectal cancer (CRC) is the second most common cause of cancer-related death and represents a serious worldwide health problem. CRC metastasis decreases the survival rate of cancer patients, underscoring the need to identify novel anticancer agents and therapeutic targets. Here, we introduce Plectalibertellenone A (B) as a promising agent for the inhibition of CRC cell motility and glucose metabolism and explore its mechanism of action in CRC cells. Plectalibertellenone A suppressed TGF-β gene expression and the activation of the TGF-β/Smad signaling pathway, leading to reverse epithelial to mesenchymal transition (EMT) by modulating the expressions of EMT markers and transcriptional factors such as E-cadherin, N-cadherin, vimentin, Slug, Snail, Twist, and ZEB1/2. Furthermore, disruption of Wnt signaling inhibited CRC motility and glucose metabolism including glycolysis and oxidative phosphorylation, primarily affecting glycolytic enzymes, GLUT1, HK2, PKM2, LDHA, and HIF-1α under hypoxic condition. Therefore, Plectalibertellenone A is a potential drug candidate that can be developed into a promising anticancer treatment to prevent CRC metastasis and inhibit glucose metabolism., (© 2024 International Union of Biochemistry and Molecular Biology.)

Background: Expression of the KITENIN/ErbB4 oncogenic complex is associated with metastasis of colorectal cancer to distant organs and lymph nodes and is linked with poor prognosis and poor survival., Methods: Here, we used in vitro and in silico methods to test the ability of chrysophanol, a molecule of natural origin, to suppress the progression of colorectal cancer by targeting the KITENIN/ErbB4 complex., Results: Chrysophanol binds to ErbB4, disrupting the ErbB4/KITENIN complex and causing autophagic degradation of KITENIN. We demonstrated that chrysophanol binds to ErbB4 according to a molecular docking model. Chrysophanol reversed KITENIN-mediated effects on cell motility, aerobic glycolysis, and expression of downstream effector genes. Moreover, under conditions of KITENIN overexpression, chrysophanol suppressed the production of onco-metabolites., Conclusion: Chrysophanol suppresses oncogenic activities by targeting the KITENIN/ErbB4 complex., (© 2024. The Author(s).)

The anticancer therapeutic effects of usnic acid (UA), a lichen secondary metabolite, have been demonstrated in vitro and in vivo . However, the mechanism underlying the anticancer effect of UA remains to be clarified. In this study, the target protein of UA was identified using a UA-linker-Affi-Gel molecule, which showed that UA binds to the 14-3-3 protein. UA binds to 14-3-3, causing the degradation of proteasomal and autophagosomal proteins. The interaction of UA with 14-3-3 isoforms modulated cell invasion, cell cycle progression, aerobic glycolysis, mitochondrial biogenesis, and the Akt/mTOR, JNK, STAT3, NF-κB, and AP-1 signaling pathways in colorectal cancer. A peptide inhibitor of 14-3-3 blocked or regressed the activity of UA and inhibited its effects. The results suggest that UA binds to 14-3-3 isoforms and suppresses cancer progression by affecting 14-3-3 targets and phosphorylated proteins., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Anithiactin D ( 1 ), a 2-phenylthiazole class of natural products, was isolated from marine mudflat-derived actinomycetes Streptomyces sp. 10A085. The chemical structure of 1 was elucidated based on the interpretation of NMR and MS data. The absolute configuration of 1 was determined by comparing the experimental and calculated electronic circular dichroism (ECD) spectral data. Anithiactin D ( 1 ) significantly decreased cancer cell migration and invasion activities at a concentration of 5 μM via downregulation of the epithelial-to-mesenchymal transition (EMT) markers in A549, AGS, and Caco-2 cell lines. Moreover, 1 inhibited the activity of Rho GTPases, including Rac1 and RhoA in the A549 cell line, suppressed RhoA in AGS and Caco-2 cell lines, and decreased the mRNA expression levels of some matrix metalloproteinases (MMPs) in AGS and Caco-2 cell lines. Thus 1 , which is a new entity of the 2-phenylthiazole class of natural products with a unique aniline-indole fused moiety, is a potent inhibitor of the motility of cancer cells.

Lung cancer has the highest mortality rates worldwide. The disease is caused by environmental pollutants, smoking, and many other factors. Recent treatments include immunotherapeutics, which have shown some success; however, the search for new therapeutics is ongoing. Endolichenic fungi produce a whale of a lot of secondary metabolites, the therapeutic effects of which are being evaluated. Here, we used a crude extract and subfractions of the endolichenic fungus, Phoma sp. (EL006848), isolated from the Pseudevernia furfuracea . It was identified the fatty acid components, palmitic acid, stearic acid, and oleic acid, exist in subfractions E1 and E2. In addition, EL006848 and its fatty acids fractions suppressed benzo[ a ]pyrene (an AhR ligand)- induced expression of PD-L1 to inhibit the activity of multiple immune checkpoints. E2 subfraction, which had a higher fatty acid content than E1, downregulated expression of AhR/ARNT and several human transcription factors related to ESR1. Moreover, E2 showed a strong inhibitory effect on STAT3 expression and mild effect on NF-kB activity. These results suggest that fatty acids extracted from an endolichenic fungus can exert strong immunotherapeutic effects., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Endolichenic fungi (ELF) produce specialized metabolites that have various medicinal properties. Inhibition of tumor angiogenesis efficaciously suppresses many types of cancer. This study aimed to discover novel antiangiogenic agents from specialized metabolite extracts of ELF strains isolated from Korean lichens. The EtOAc extracts of 51 ELF strains were subjected to a screening pipeline consisting of cell viability, scratch wound healing, and Transwell migration assays. The EtOAc extract of Arthrinium sp. EL000127 showed the most potent inhibitory activity against the chemotactic migration of human umbilical vein endothelial cells (HUVEC). Targeted isolation on the major LC-MS peaks exhibited a previously known phthalide, 3- O -methylcyclopolic acid ( 1 ), and two unknown analogues of 1 , 3- O -phenylethylcyclopolic acid ( 2 ) and 3- O - p -hydroxyphenylethylcyclopolic acid ( 3 ). The structures were characterized by MS and NMR analyses. All the isolates were acquired and applied to bioassays as racemates due to spontaneous racemization. Among the isolates, compound 3 effectively inhibits HUVEC motility by suppressing mRNA expressions of genes regulating epithelial cell survival and motility, which suggested that compound 3 is a potent antiangiogenic agent suitable for further exploration as a potential novel therapeutic against cancers., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Marinobazzanan ( 1 ), a new bazzanane-type sesquiterpenoid, was isolated from a marine-derived fungus belonging to the genus Acremonium . The chemical structure of 1 was elucidated using NMR and mass spectroscopic data, while the relative configurations were established through the analysis of NOESY data. The absolute configurations of 1 were determined by the modified Mosher's method as well as vibrational circular dichroism (VCD) spectra calculation and it was determined as 6 R , 7 R , 9 R , and 10 R . It was found that compound 1 was not cytotoxic to human cancer cells, including A549 (lung cancer), AGS (gastric cancer), and Caco-2 (colorectal cancer) below the concentration of 25 μM. However, compound 1 was shown to significantly decrease cancer-cell migration and invasion and soft-agar colony-formation ability at concentrations ranging from 1 to 5 μM by downregulating the expression level of KITENIN and upregulating the expression level of KAI1. Compound 1 suppressed β-catenin-mediated TOPFLASH activity and its downstream targets in AGS, A549, and Caco-2 and slightly suppressed the Notch signal pathway in three cancer cells. Furthermore, 1 also reduced the number of metastatic nodules in an intraperitoneal xenograft mouse model.

Endolichenic fungi are host organisms that live on lichens and produce a wide variety of secondary metabolites. Colorectal cancer stem cells are capable of self-renewal and differentiation into cancer cells, which makes cancers difficult to eradicate. New alternative therapeutics are needed to inhibit the growth of tumor stem cells. This study examined the ability of an extract of Jackrogersella sp. EL001672 (derived from the lichen Cetraria sp.) and the isolated compound 1'-O-methyl-averantin to inhibit development of cancer stemness. The endolichenic fungus Jackrogersella sp. EL001672 (KACC 83021BP), derived from Cetraria sp., was grown in culture medium. The culture broth was extracted with acetone to obtain a crude extract. Column chromatography and reverse-phase HPLC were used to isolate an active compound. The anticancer activity of the extract and the isolated compound was evaluated by qRT-PCR and western blotting, and in cell viability, spheroid formation, and reporter assays. The acetone extract of EL001672 did not affect cell viability. However, 1'-O-methyl-averantin showed cytotoxic effects against cancer cell lines at 50 μg/mL and 25 μg/mL. Both the crude extract and 1'-O-methyl-averantin suppressed spheroid formation in CRC cell lines, and downregulated expression of stemness markers ALDH1, CD44, CD133, Lgr-5, Msi-1, and EphB1. To further characterize the mechanism underlying anti-stemness activity, we examined sonic Hedgehog and Notch signaling. The results showed that the crude extract and the 1'-O-methyl-averantin inhibited Gli1, Gli2, SMO, Bmi-1, Notch-1, Hes-1, and the CSL complex. Consequently, an acetone extract and 1'-O-methyl-averantin isolated from EL001672 suppresses colorectal cancer stemness by regulating the sonic Hedgehog and Notch signaling pathways., (© 2023. The Author(s).)

Colorectal cancer (CRC) is the third most deadly type of cancer in the world and continuous investigations are required to discover novel therapeutics for CRC. Induction of apoptosis is one of the promising strategies to inhibit cancers. Here, we have identified a novel compound, Libertellenone T ( B ), isolated from crude extracts of the endolichenic fungus from Pseudoplectania sp. (EL000327) and investigated the mechanism of action. CRC cells treated by B were subjected to apoptosis detection assays, immunofluorescence imaging, and molecular analyses such as immunoblotting and QRT-PCR. Our findings revealed that B induced CRC cell death via multiple mechanisms including G2/M phase arrest caused by microtubule stabilization and caspase-dependent apoptosis. Further studies revealed that B induced the generation of reactive oxygen species (ROS) attributed to activating the JNK signaling pathway by which apoptosis and autophagy was induced in Caco2 cells. Moreover, B exhibited good synergistic effects when combined with the well-known anticancer drug, 5-FU, and another cytotoxic novel compound D, which was isolated from the same crude extract of EL000327. Overall, Libertellenone T induces G2/M phase arrest, apoptosis, and autophagy via activating the ROS/JNK pathway in CRC. Thus, B may be a potential anticancer therapeutic against CRC that is suitable for clinical applications.

Background: Endolichenic fungi (ELF), which live the inside the lichen thallus, contain many secondary metabolites that show various biological activities. Recent studies show that lichen and ELF secondary metabolites have antioxidant, antibacterial, antifungal, cytotoxic, and anticancer activities. Purpose: Here, the effects of an ELF extract and its bioactive compounds were investigated on the H1975 cell line focusing on immune checkpoint marker inhibition. Methods: An ELF was isolated from the host lichen Bryoria fuscescens (Gyelnik) Brodo and D. Hawksw and identified the species as Nemania sp. EL006872. The fungus was cultured on agar medium and acetonic extracts were obtained. Secondary metabolites radianspenes C and D, and dahliane D, were isolated from the crude extract. The biological effects of both the crude extract and the isolated secondary metabolites were evaluated in cell viability, qRT-PCR assays, flow cytometry analysis and western blotting. Results: The cell viability assay revealed that extracts from Nemania sp. EL006872 and the isolated secondary compounds had low cytotoxicity. The crude extract, radianspenes C and D, and dahliane D, suppressed expression of mRNA encoding PD-L1 and aromatic hydrocarbon receptor (AhR), and surface expression of PD-L1 protein by cells exposed to benzo[a] pyrene. Radianspenes C and D, and dahliane D, reduced expression of AhR, PD-L1, ICOSL, and GITRL proteins by H1975 lung cancer cells, as well as exerting anti-proliferative effects. Conclusion: Radianspenes C and D, and dahliane D, bioactive compounds isolated from Nemania sp. EL006872 ELF, have the potential for use as immunotherapy and immunoncology treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Varlı, Pham, Kim, Taş, Gamage, Zhou, Pulat, Park, Sesal, Hur, Kang and Kim.)

Background: Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action., Purpose: We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC)., Methods: The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western blotting, immunohistochemistry in vitro; and by tumorigenicity study with orthotopic breast cancer xenograft model in vivo., Results: PHY markedly inhibited BC cell viability. Cell-cycle profiling and Annexin V-FITC/PI double staining showed that a toxic dosage of PHY triggered apoptosis in BC cell lines by regulating the B-cell lymphoma-2 (Bcl-2) family proteins and the activity of caspase pathway. At non-toxic concentrations, PHY potently decreased migration, proliferation, and tumorigenesis of BC cells in vitro. Metabolic studies revealed that PHY treatment significantly reduced the bioenergetic profile by decreasing respiration, ATP production, and glycolysis capacity. In addition, PHY significantly altered the levels of mitochondrial (PGC-1α) and glycolysis (GLUT1, HK2 and PKM2) markers, and downregulated transcriptional regulators involved in cancer cell metabolism, including β-catenin, c-Myc, HIF-1α, and NF-κB. An orthotopic implantation mouse model of BC confirmed that PHY treatment suppressed BC growth in vivo and target genes were consistently suppressed in tumor specimens., Conclusion: The findings from our in vitro as well as in vivo studies exhibit that PHY suppresses energy metabolism as well as tumorigenesis in BC. Especially, PHY represents a promising therapeutic effect against hormone-insensitive BC (triple negative) by targeting energy metabolism., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

A cyclic tetrapeptide, androsamide ( 1 ), was isolated from a marine actinomycete of the genus Nocardiopsis , strain CNT-189. The planar structure of 1 was assigned by the interpretation of 1D and 2D NMR spectroscopic data. The absolute configurations of constituent amino acids of 1 were determined by application of the Marfey's and advanced Marfey's methods. Androsamide ( 1 ) strongly suppressed the motility of Caco2 cells caused by epithelial-mesenchymal transition.

Exposure to environmental pollutants is a major public health concern. This study investigated the inflammatory and tumorigenic effects of environmental pollutants (benzene, benzo[a]pyrene, cadmium, and diisononyl phthalate) on transformed A549 and H292 lung alveolar epithelial cells and non-transformed BEAS-2B lung bronchial epithelial cells. The cytotoxic effects of the pollutants were analyzed by the methyl thiazolyl tetrazolium assay. The anchorage-independent soft agar assay demonstrated that treatment with benzene, cadmium, and diisononyl phthalate for 4 weeks induced malignant transformation of BEAS-2B cells and tumorigenesis of A549 and H292 cells. mRNA expression of the inflammation-related genes tenascin-C, matrix metalloproteinase (MMP)-9, and MMP-2, as well as inhibitors of MMPs (TIMP-1 and TIMP-2), was analyzed by RT-PCR. The pollutants largely upregulated expression of MMP-9 and MMP-2, but suppressed expression of their inhibitors TIMP-1 and TIMP-2. Measurement of transepithelial electrical resistance revealed that cadmium and diisononyl phthalate significantly increased cell permeability. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor of inflammatory genes, including MMP-9 and MMP-2, while signal transducer and activator of transcription (STAT) 3 is a key regulator of malignant transformation. All the pollutants activated the NF-κB promoter, while only cadmium induced activation of the STAT3 promoter in HEK293T cells. Moreover, all the pollutants increased the phospho-NF-κB level, but only cadmium and diisononyl phthalate increased the phospho-STAT3 level in A549 and BEAS-2B cells. These findings suggest that specific environmental pollutants enhance inflammation, cell permeability, and malignant transformation in lung epithelial cells by activating the oncogenic transcription factors STAT3 and NF-κB., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Deoxypodophyllotoxin (DPT) is a cyclolignan compound that exerts anti-cancer effects against various types of cancers. DPT induces apoptosis and inhibits the growth of breast, brain, prostate, gastric, lung, and cervical tumors. In this study, we sought to determine the effect of DPT on cell proliferation, apoptosis, motility, and tumorigenesis of three colorectal cancer (CRC) cell lines: HT29, DLD1, and Caco2. DPT inhibited the proliferation of these cells. Specifically, the compound-induced mitotic arrest in CRC cells by destabilizing microtubules and activating the mitochondrial apoptotic pathway via regulation of B-cell lymphoma 2 (Bcl-2) family proteins (increasing Bcl-2 associated X (BAX) and decreasing B-cell lymphoma-extra-large (Bcl-xL)) ultimately led to caspase-mediated apoptosis. In addition, DPT inhibited tumorigenesis in vitro, and in vivo skin xenograft experiments revealed that DPT significantly decreased tumor size and tumor weight. Taken together, our results suggest DPT to be a potent compound that is suitable for further exploration as a novel chemotherapeutic for human CRC.

Background: Lichens, which represent symbiotic associations of fungi and algae, are potential sources of numerous natural products. Physciosporin (PHY) is a potent secondary metabolite found in lichens and was recently reported to inhibit the motility of lung cancer cells via novel mechanisms., Purpose: The present study investigated the anticancer potential of PHY on colorectal cancer (CRC) cells., Methods: PHY was isolated from lichen extract by preparative TLC. The effect of PHY on cell viability, motility and tumourigenicity was elucidated by MTT assay, hoechst staining, flow cytometric analysis, transwell invasion and migration assay, soft agar colony formation assay, Western blotting, qRT-PCR and PCR array in vitro as well as tumorigenicity study in vivo., Results: PHY decreased the viability of various CRC cell lines (Caco2, CT26, DLD1, HCT116 and SW620). Moreover, PHY elicited cytotoxic effects by inducing apoptosis at toxic concentrations. At non-toxic concentrations, PHY dose-dependently suppressed the invasion, migration and colony formation of CRC cells. PHY inhibited the motility of CRC cells by suppressing epithelial-mesenchymal transition and downregulating actin-based motility markers. In addition, PHY downregulated β-catenin and its downstream target genes cyclin-D1 and c-Myc. Moreover, PHY modulated KAI1 C-terminal-interacting tetraspanin and KAI1 expression, and downregulated the downstream transcription factors c-jun and c-fos. Finally, PHY administration showed considerable bioavailability and effectively decreased the growth of CRC xenografts in mice without causing toxicity., Conclusion: PHY suppresses the growth and motility of CRC cells via novel mechanisms., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Lichens produce various unique chemicals that are used in the pharmaceutical industry. To screen for novel lichen secondary metabolites that inhibit the stemness potential of colorectal cancer cells, we tested acetone extracts of 11 lichen samples collected in Chile. Tumidulin, isolated from Niebla sp., reduced spheroid formation in CSC221, DLD1, and HT29 cells. In addition, mRNA expressions and protein levels of cancer stem markers aldehyde dehydrogenase-1 (ALDH1), cluster of differentiation 133 (CD133), CD44, Lgr5, and Musashi-1 were reduced after tumidulin treatment. Tumidulin decreased the transcriptional activity of the glioma-associated oncogene homolog zinc finger protein (Gli) promoter in reporter assays, and western blotting confirmed decreased Gli1, Gli2, and Smoothened (SMO) protein levels. Moreover, the tumidulin activity was not observed in the presence of Gli and SMO inhibitors. Together, these results demonstrate for the first time that tumidulin is a potent inhibitor of colorectal cancer cell stemness.