GW4064 inhibits migration and invasion in human glioblastoma multiforme through the downregulation of PKCα.

in European journal of pharmacology by Yi-Hsuan Lin, Tzu-Min Chen, Chien-Rui Lai, Yu-Ling Tsai, Wen-Chiuan Tsai, Ying Chen

TLDR

  • GW4064, a bile acid nuclear receptor agonist, inhibits GBM cell migration and invasion, and may be a useful addition to current treatments.
  • Combining GW4064 with temozolomide, a common GBM treatment, shows promising results in reducing tumor progression.

Abstract

Glioblastoma multiforme (GBM) is a deadly type of brain tumor with low patient survival rates. Previous studies have shown that inhibiting the intracellular bile acid transport protein can suppress brain tumor growth, migration, and angiogenesis. This study aims to investigate the effects of the bile acid nuclear receptor (farnesoid X receptor, FXR) agonist GW4064 on the migration, and invasion in GBM cells. GW4064 treatment inhibited the migration and invasion of GBM cells. The protein expression of phosphorylated focal adhesion kinase and protein kinase C alpha (PKCα) and activity of matrix metalloproteinase-2 (MMP2) were decreased by GW4064. The PKC activator phorbol 12-myristate 13-acetate (PMA) reversed the GW4064-reduced invasion ability in LN229 cells. Moreover, GW4064 combined with temozolomide (TMZ) treatment inhibited tumor progression in null mice. According to the hematoxylin and eosin stain (HE) and immunostaining, the tumor area and p-PKCα were reduced in the GW4064 combined with TMZ group. These results suggested that GW4064 declined the progression of GBM cells, with the inhibition of invasion mediated through PKC signaling. Targeting FXR may contribute to future therapeutic strategies for GBM.

Overview

  • The study investigates the effects of the bile acid nuclear receptor agonist GW4064 on the migration and invasion of Glioblastoma multiforme (GBM) cells.
  • The study aims to determine if GW4064 can inhibit the migration and invasion of GBM cells and if it can be a potential therapeutic strategy for GBM treatment.
  • The study uses both in vitro and in vivo experiments to test the effects of GW4064 on GBM cells and to see if it can be combined with other treatments for better results.

Comparative Analysis & Findings

  • The study found that GW4064 treatment inhibited the migration and invasion of GBM cells, and decreased the protein expression of phosphorylated focal adhesion kinase and protein kinase C alpha (PKCα) and activity of matrix metalloproteinase-2 (MMP2).
  • The phorbol 12-myristate 13-acetate (PMA) activator of PKC reversed the GW4064-reduced invasion ability in LN229 cells, suggesting that PKC signaling is involved in the inhibition of invasion by GW4064.
  • Combining GW4064 with temozolomide (TMZ) treatment inhibited tumor progression in nude mice, and reduced the tumor area and p-PKCα in the GW4064 combined with TMZ group compared to the TMZ group.

Implications and Future Directions

  • The study suggests that targeting the bile acid nuclear receptor FXR with GW4064 may be a potential therapeutic strategy for GBM treatment, especially when combined with other treatments like TMZ.
  • Future studies should investigate the mechanisms by which GX4064 inhibits invasion and migration of GBM cells, and how it interacts with other signaling pathways to affect cell behavior.
  • Clinical trials are needed to evaluate the safety and efficacy of GW4064 as a treatment for GBM patients.
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