Figure 3

Hypoxic activation of apoptosis pathways. Hypoxia activates intracellular signalling pathways involved in apoptosis and cell survival. One pathway of particular importance is hypoxia-induced mitochondrial membrane permability, leading to subsequent release of cytochrome C into the cytoplasm. Cytochrome C initiates the apoptosis cascade via activation of the apoptosis kinase Apaf-1, which in turn activates the caspase 9 apoptosis pathway. Hypoxia also activates JNK/SAPK signalling pathways which leads to apoptosis induction by an as yet unknown mechanism. The protein kinase Akt plays a central role in cell survival via induction of anti-apoptotic mechanisms, involving the anti-apoptotic function of Bcl-xL. Akt is also involved in hypoxia-induced HIF-dependent VEGF expression, a signalling cascade that can be inhibited by the tumor suppressor PTEN. PTEN exerts its negative regulatory effects via inhibition of phosphatidylinositol (3,4) and phosphatidylinositol (3,4,5) phosphorylation. Late-stage tumors often display mutated PTEN or show a complete loss of PTEN expression, which leads to a de-repression of the survival phosphatidylinositol (PtdIns) 3-kinase-Akt signalling pathway. PDK, PtdIns (3,4,5)P₃-dependent kinase.