Cell death in glioblastoma and the central nervous system

Abstract

Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.

Keywords: Apoptosis; Astrocytes; Glioblastoma; Inhibitor of Apoptosis; Necroptosis; Oligodendrocytes.

Fig. 1

Intrinsic apoptotic pathway. DNA damaging agents including chemotherapy and radiation induce expression of pro-apoptotic BH3-only proteins, exceeding the balance with anti-apoptotic BCL-2 family proteins and permitting BAX and BAK oligomerization in the mitochondrial outer membrane. This outer membrane is consequently permeabilized, allowing release of pro-apoptotic factors including Apaf-1 and Cytochrome C, which form the apoptosome with CASP9 and cleave downstream effector CASP3 and CASP7. SMAC release from the mitochondria inhibits XIAP, a crucial step in permitting apoptosis

Fig. 2

Death receptor apoptotic pathway. Engagement of TNFR superfamily death receptors (TRAILR1/2 (DR4/5), FAS, TNFR1) by their ligands (TRAIL, FasL, TNF-α) leads to FADD recruitment. FADD in turn recruits multiple pro-CASP8 monomers, forming the DISC/Faddosome/Ripoptosome. Pro-CASP8 cleavage to activated CASP8 leads to cleavage and activation of CASP3 and CASP7, effecting apoptosis and cleavage of Bid to tBiD, engaging the intrinsic apoptotic pathway. cFLIP binding FADD inhibits subsequent pro-CASP8 binding and DISC or DIC2 formation. In TNFR1 signaling, TRADD and RIPK1 are initially recruited following TNF-α binding. TRAF2/3 is subsequently recruited, and in turn recruits cIAP1/2 which ubiquitinate RIPK1. This ubiquitinated RIPK1 represents a scaffold for downstream signaling to activate IKK to degrade IκBα, permitting NF-κB activation. In the absence of cIAP1/2, lack of RIPK1 ubiquitination results in recruitment of FADD by TRADD and formation of the DIC2. Engagement of death receptors in the absence of CASP8 results in CYLD or A20 deubiquitination of RIPK1 and RIPK3 and consequent RIPK1-RIPK3-MLKL dependent necroptosis