Mechanisms of Cell Cycle Arrest and Apoptosis in Glioblastoma

Abstract

Cells of glioblastoma, the most frequent primary malignant brain tumor, are characterized by their rapid growth and infiltration of adjacent healthy brain parenchyma, which reflects their aggressive biological behavior. In order to maintain their excessive proliferation and invasion, glioblastomas exploit the innate biological capacities of the patients suffering from this tumor. The pathways involved in cell cycle regulation and apoptosis are the mechanisms most commonly affected. The following work reviews the regulatory pathways of cell growth in general as well as the dysregulated cell cycle and apoptosis relevant mechanisms observed in glioblastomas. We then describe the molecular targeting of the current established adjuvant therapy and present ongoing trials or completed studies on specific promising therapeutic agents that induce cell cycle arrest and apoptosis of glioblastoma cells.

Keywords: Karyopherin a2 (KPNA2); Rb pathway; apoptosis; cell cycle arrest; exportin 1 (XPO1); glioblastoma; ion channels; nucleocytoplasmic shuttling; p53 pathway.

Figure 1

Cell cycle cascades. The cells enter the cell cycle after transcription of released E2F in the nucleus, which is promoted by the phosphorylation of Rb in the context of the interaction between various cyclins–CDKs complexes and Rb. The contrary complex CDKIs–CDKs inhibits the phosphorylation of Rb. Consequently, Rb and E2F are not released from chromatin but still bind to a firm complex, which leads to cell cycle arrest. Abbreviations: CDKs: cyclin-dependent kinases; CDKIs: cyclin-dependent kinases inhibitor; Rb: retinoblastoma, rE2F: released E2F. Most known cyclins: cyclin A, B1, B2, D1, D2, D3, E1, E2, G1; CDKs: CDK1, 2, 4, 6, 9; CDKIs: p16, p21, p27, p57.

Figure 2

Pathways of apoptosis. Depiction of the cascades of apoptosis. Diverse internal and external stimuli causing persistent damage signaling, such as DNA damage, cellular stress, telomere shortening, ionizing radiation, mitochondrial dysfunction, heat, hypoxia, may trigger the process of apoptosis via the perforin/granzyme (A), extrinsic (B) or intrinsic/mitochondrial (C) pathway. The aforementioned processes activate the final step of apoptosis, named the executive pathway of apoptosis (D). During these procedures, initiators (caspases 8, 9, 10) and effectors caspases (caspases 3, 6, 7) are key players in the degradation of critical cell structures until the phagocytosis of the apoptotic cell. Under physiological conditions, p53 activity is controlled by MGM2; in the case of severe permanent damage, signaling p53 is upregulated and triggers the extrinsic and intrinsic pathway of apoptosis. Abbreviations: FADD: Fas-associated protein with death domain; TRADD: tumor necrosis factor receptor type1-associated death domain protein; MGM2: mouse double minute 2; Apaf-1: apoptotic protease-activating factor 1; TNFa: tumor necrosis factor alpha; TNF-R: tumor necrosis factor alpha receptor. Common ligand bindings of the extrinsic pathway are TNFa/TNF-Rs, ApoLs/DRs, TRAIL/TRAIL-Rs, FasL-Fas-R. Known proapoptotic proteins: Bcl-10, Bax, Bak, Bad; antiapoptotic proteins: Bcl-2, Bcl-x, BAG.

Figure 3

Interactions between pathways of p53 and NF-kB in GBM. Similar stimuli trigger NF-kB and p53 pathways. In turn, several interactions between the aforementioned cascades are observed in multiple levels at their cytoplasmic as well as their nuclear localization, resulting in cell cycle arrest, apoptosis, neuroinflammation, impaired EGFR signaling, and angiogenesis in GBM. The subcellular translocation is performed by karyopherins (nuclear import: KPNA2; nuclear export: CRM1/XPO1).

Figure 4

Molecular targeting of GBM therapeutic agents. The current figure depicts the molecular targets of potential therapeutic agents for GBM within the pathways of apoptosis and cell cycle (arrow: upregulation; line: downregulation).