Libertellenone T, a Novel Compound Isolated from Endolichenic Fungus, Induces G2/M Phase Arrest, Apoptosis, and Autophagy by Activating the ROS/JNK Pathway in Colorectal Cancer Cells

Abstract

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.

Usnic Acid Targets 14-3-3 Proteins and Suppresses Cancer Progression by Blocking Substrate Interaction

“…Conversion of LC3B-I to LC3B-II and binding of LC3B to p62 facilitate autophagic degradation. 58 Current results indicate that the activity of UA involves the regulation of 14-3-3 proteins, which is consistent with previous reports of the effect of UA on signaling pathways related to cell death.…”

“…14-3-3 proteins bind to TSC2 and PRAS40, which act as mTOR regulators, thereby playing a role in mTOR-regulated cellular processes. , UA induces autophagy and apoptosis by inhibiting the AKT, mTOR, ERK1/2, and JNK signaling pathways. , Important regulators of the autophagic process include P62 and LC3B-I/II. Conversion of LC3B-I to LC3B-II and binding of LC3B to p62 facilitate autophagic degradation . Current results indicate that the activity of UA involves the regulation of 14-3-3 proteins, which is consistent with previous reports of the effect of UA on signaling pathways related to cell death.…”

“…Pellets were resuspended in 100 μL of 4 mg/mL PI (Sigma-Aldrich, St. Louis, MO, USA) and incubated for 2 h in the dark at 4 °C. Flow cytometry was performed with a CytoFLEX instrument (Beckman Coulter Life Sciences) …”

Actinoquinazolinone, a New Quinazolinone Derivative from a Marine Bacterium Streptomyces sp. CNQ-617, Suppresses the Motility of Gastric Cancer Cells

“…Using a Moloney Murine Leukemia Virus (M-MLV) kit, total RNA (1 µg) from DMSO as well as 1 and 5 μM of treatment with compound 1 groups were converted to cDNA. SYBR Green (Enzynomics, Seoul, Republic of Korea) was used to evaluate relative gene expression and CFX (Bio-Rad, Hercules, CA, USA) was applied for analysis [ 90 , 91 ].…”

Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases

“…The latest findings show that bacterial extracellular vesicles induced mitophagy through mTOR pathways relieve oxidative stress in colonic epithelial cells[ 21 ]. Libertellenone T, a compound isolated from Endolichenic fungus , also induces autophagy to strengthen the epithelial barrier function of the colon[ 22 ].…”