Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2

Abstract

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.

Biomineralized Polydopamine Nanoparticle-Based Sodium Alginate Hydrogels for Delivery of Anti-serine/Threonine Protein Kinase B-Rapidly Accelerated Fibrosarcoma siRNA for Metastatic Melanoma Therapy

“…Another important antitumor mechanism is strongly related to siBRAF. The RAF family, particularly in cases where RAF mutates in malignant melanoma, plays an important role in the MAPK signaling pathway . BRAF is a member of the RAF family that can increase the phosphorylated ERK level without needing upstream RAS activation .…”

“…The RAF family, particularly in cases where RAF mutates in malignant melanoma, plays an important role in the MAPK signaling pathway. 35 BRAF is a member of the RAF family that can increase the phosphorylated ERK level without needing upstream RAS activation. 36 Phosphorylated ERK tends to be transported to the nucleus, where it can alter the expression of related genes, leading to tumor cell proliferation, invasion, metastasis, and resistance to cell death.…”

TPI1 promotes MAPK/ERK‐induced EMT, cell migration and invasion in lung adenocarcinoma

“…Activated ERK translocates to the nucleus, where it modulates the activity of various transcription factors, such as Snail, Slug, and Twist. These transcription factors, in turn, regulate the expression of genes involved in EMT, causing downregulation of epithelial markers such as E‐cadherin and upregulation of mesenchymal markers such as N‐cadherin and vimentin 34–36 . The overall effect is a phenotypic shift in cells from an epithelial to a mesenchymal state, promoting enhanced cellular motility, invasiveness, and metastatic potential.…”

Mechanism of Erianin anti-triple negative breast cancer based on transcriptomics methods and network pharmacology

“…When the tumor size reached approximately 15 mm 3 , all mice were randomly divided into two groups: the experimental group and the control group (five mice in each group). The mice in the experimental group were injected with 4 mg/kg Erianin (based on previous studies [9,12,[18][19][20][21][22][23] and our experimental validation), while the control group received an injection of the same volume of 1% DMSO. Every two days, the tumor volume was measured.…”