# Reprogramming the Apoptosis–Autophagy Axis in Glioblastoma: The Central Role of the Bcl-2:Beclin-1 Complex and Survival Signalling Networks

## TL;DR

This paper explores how glioblastoma evades treatment by switching between cell death and survival processes, focusing on a key protein complex and signaling pathways.

## Contribution

The paper introduces a systems-level view of how the Bcl-2:beclin-1 complex and survival signaling networks regulate cell death in glioblastoma.

## Key findings

- The Bcl-2:beclin-1 complex acts as a molecular switch controlling apoptosis and autophagy in glioblastoma.
- Survival signaling networks like PI3K/AKT/mTOR and Ras/Raf/MEK/ERK regulate the balance between cell death and survival.
- Targeting the Bcl-2:beclin-1 complex and its regulators may improve glioblastoma treatment responses.

## Abstract

Glioblastoma multiforme (GBM) exhibits remarkable resistance to therapy, mainly due to its capacity to modulate regulated cell death pathways. Among these, apoptosis and autophagy are dynamically interconnected, determining cell fate under therapeutic stress. The interaction between beclin-1 and Bcl-2 proteins may represent a key molecular switch that controls whether glioma cells undergo survival or death. This review highlights the crucial role of the Bcl-2:beclin-1 complex in controlling apoptosis–autophagy axis in GBM, emphasising how survival signalling networks, including PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and PLCγ1/PKC pathways regulated by the TrkB receptor, modulate this balance. We summarise recent insights into how these pathways coordinate the shift between apoptosis and autophagy in glioma cells, contributing to drug resistance. Furthermore, we highlight how modulating this crosstalk can sensitise GBM to conventional and emerging therapies. Integrating new concepts of cell death reprogramming and systems-level signalling analysis, we propose that targeting the Bcl-2:beclin-1 complex and its upstream regulators could overcome the adaptive plasticity of glioblastoma multiforme and open new directions for combination treatment strategies.