4.7 Article

GPR17 signaling activation by CHBC agonist induced cell death via modulation of MAPK pathway in glioblastoma

Journal

LIFE SCIENCES
Volume 291, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2022.120307

Keywords

Glioblastoma multiforme; Indole derivative; Mechanism of action; Apoptosis; MAPK pathway

Funding

  1. Academy of Finland [326487, 326486]
  2. Fundacao para a Ciencia e Tecnologia [CEE-CINST/00026/2018]
  3. TUNI
  4. Janne and Aatos Erkko Foundation
  5. Academy of Finland (AKA) [326486, 326486] Funding Source: Academy of Finland (AKA)

Ask authors/readers for more resources

The study demonstrates that CHBC induces G2/M cell cycle arrest and apoptosis by disrupting MAPK signaling in human glioblastoma cells. CHBC could potentially be a class of compounds for treating glioblastoma.
Aim: Glioblastoma multiforme (GBM) is the most common and aggressive primary adult brain tumor. GBM is characterized by a heterogeneous population of cells that are resistant to chemotherapy. Recently, we have synthesized CHBC, a novel indole derivative targeted to GBM biomarker G-protein-coupled receptor 17 and inhibitor of GBM cells. In this study, CHBC was further investigated to characterize the efficiency of this agonist at the molecular level and its underlying mechanism in GBM cell death induction. Materials and methods: The effect of CHBC and TMZ was determined using time dependent inhibitor assay in glioblastoma cells, LN229 and SNB19. Drug induced cell cycle arrest was measured using PI staining followed by image analysis. The induction of apoptosis and mechanism of action of CHBC was studied using apoptosis, caspase 3/7 and mitochondrial membrane permeability assays. Modulation of the key genes involved in MAPK signaling pathway was also measured using immunoblotting array. Key findings: The inhibitory kinetic study has revealed that CHBC inhibited SNB19 and LN229 cell growth in a time-dependent manner. Furthermore, CHBC with the IC50 of 85 mu m, mediated cell death through an apoptosis mechanism in both studied cell lines. The study also has revealed that CHBC targets GPR17 leading to the induction of apoptosis via the activation of Caspase 3/7 and dysfunction of mitochondrial membrane potential. In addition, CHBC treatment led to marked G2/M cell cycle arrest. The protein array has confirmed the anticancer effect of CHBC by the disruption of the mitogen-activated protein kinase pathway (MAPK). Significance: Taken together, these results demonstrated that CHBC induced G2/M cell cycle arrest and apoptosis by disrupting MAPK signaling in human glioblastoma cells. This study concludes that CHBC represent a class of compounds for treating glioblastoma.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available