Apoptotic Signaling Pathways in Glioblastoma and Therapeutic Implications

Figure 1

Apoptotic Pathways in Glioblastoma. (A) The activation of PI3K ensues by the binding of a ligand to a receptor tyrosine kinase (RTK). The RTK activation by phosphorylation of its intracellular domain activates the catalytic subunit of PI3K; this results in the generation of PIP₃ from PIP₂. PIP₃ activates PDK1 which in turn phosphorylates AKT. AKT phosphorylates many downstream targets, including IκB to induce NFκB activation and mTORC2 and MDM2 to induce cell survival. PTEN antagonizes the PI3K pathway by dephosphorylating the second messenger PIP₃ to PIP₂. (B) TNF-α is a potent activator of NFκB, which binds to its receptor (TNFR1) enabling the degradation of IκB, by the IKK complex. This allows the translocation of NFκB to the nucleus where it regulates the expression of its target genes such as IAPs, which can directly bind and inhibit caspase-3, caspase-7, and caspase-9. (C) A variety of death stimuli can induce the release of cytochrome C from the mitochondria and trigger the formation of the apoptosome with subsequent caspase cascade activation leading to apoptosis. BCL-2 controls the mitochondrial membrane permeability and can inhibit this process, whereas BAX stimulates it. BAX is activated by p53 but p53 is negatively regulated by MDM2. Smac is located within the mitochondrial intermembrane space and enters the cytosol when cells undergo apoptosis to inhibit IAPs. Blue arrows denote overexpression and red arrows denote loss of function.