erianin and Colorectal-Neoplasms

Constitutive activation of RAS-RAF-MEK-ERK signaling pathway (MAPK pathway) frequently occurs in many cancers harboring RAS or RAF oncogenic mutations. Because of the paradoxical activation induced by a single use of BRAF or MEK inhibitors, dual-target RAF and MEK treatment is thought to be a promising strategy. In this work, we evaluated erianin is a novel inhibitor of CRAF and MEK1/2 kinases, thus suppressing constitutive activation of the MAPK signaling pathway induced by BRAF V600E or RAS mutations. KinaseProfiler enzyme profiling, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), cellular thermal shift assay, computational docking, and molecular dynamics simulations were utilized to screen and identify erianin binding to CRAF and MEK1/2. Kinase assay, luminescent ADP detection assay, and enzyme kinetics assay were investigated to identify the efficiency of erianin in CRAF and MEK1/2 kinase activity. Notably, erianin suppressed BRAF V600E or RAS mutant melanoma and colorectal cancer cell by inhibiting MEK1/2 and CRAF but not BRAF kinase activity. Moreover, erianin attenuated melanoma and colorectal cancer in vivo. Overall, we provide a promising leading compound for BRAF V600E or RAS mutant melanoma and colorectal cancer through dual targeting of CRAF and MEK1/2.

Topics: Colorectal Neoplasms; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Signal Transduction

Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Approximately 40% of CRC patients are KRAS sequence variation, including KRAS G13D mutation (KRAS

Topics: Autophagy; Colorectal Neoplasms; Ferroptosis; Humans; Mutation; Proto-Oncogene Proteins p21(ras)

To investigate the effect of erianin on tumor growth and immune response in human colorectal cancer cells (CRC).. The effect of erianin on tumor growth was determined by CCK8 and colony formation assay. Western blotting was used to evaluate the expression levels of relevant proteins and qRT-PCR was used to evaluate the mRNA level of the relevant gene. The transcriptional activity of β-catenin was determined by dual-luciferase reporter assay. Cellular thermal shift assay was used to quantify drug-target interactions. The cell surface CD47 was assessed by flow cytometry. The enrichment of H3K27 acetyl marks on CD47 promoter was evaluated by chromatin immunoprecipitation assay. Phagocytosis assay was used to determine the phagocytic activity of macrophage. In vivo role of erianin was studied on xenograft models.. We found that erianin significantly decreased cell survival, colony formation, induced cell cycle arrest, and led to cell apoptosis in SW480 and HCT116 cells. Mechanism analysis demonstrated that erianin inhibited the nuclear translocation and transcriptional activity of β-catenin, which might result from erianin-β-catenin interaction. In addition, the downstream gene expressions, such as c-Myc and cyclin D1, was decreased. More interestingly, erianin decreased the expression of CD47 by regulating H3K27 acetyl marks enrichment on CD47 promoter. Consequently, macrophage-mediated phagocytosis was increased. Our in vivo experiments further confirmed the inhibitory effect of erianin on tumor growth.. In summary, erianin could inhibit CRC cells growth and promoted phagocytosis, which suggested erianin as a potential therapeutic strategy for CRC patients.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Bibenzyls; Cell Cycle Checkpoints; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Dendrobium; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Structure; Neoplasms, Experimental; Phagocytosis; Phenol; Structure-Activity Relationship; Tumor Cells, Cultured