Targeting Metabolism to Induce Cell Death in Cancer Cells and Cancer Stem Cells

Figure 2

Intrinsic and extrinsic apoptotic pathways. Apoptosis can be triggered by the intrinsic mitochondrial pathway or through the extrinsic pathway involving the death receptors. The intrinsic apoptotic pathway is activated in response to various stimuli such as DNA damage, endoplasmic reticulum (ER) stress, or hypoxia. This pathway is mainly modulated through differential interactions between the antiapoptotic (Bcl-2, Bcl-XL), the proapoptotic (Bax, Bak), and the BH3-only proteins (Bad, Bid, Bim…). Bax, Bid, and Bim are initially inactive and must translocate to the mitochondria to induce apoptosis, either by binding via BH3 domains to Bcl-2, Bcl-XL and antagonizing their antiapoptotic functions or through the permeabilization of the mitochondrial membrane. Permeabilization of the mitochondrial membrane releases apoptogenic proteins, among which the cytochrome c is leading to the formation of the apoptosome, activation of caspase 9, and ultimately to the activation of effector caspases. In the extrinsic pathway, ligands (TNF, FASL, or TRAIL) bind to their specific death receptors, which lead to their oligomerization, recruitment of procaspase 8, and a specific adaptor protein (FADD and TRADD). The formation of the DISC induces autocatalysis of procaspase 8 into its active form, which in turn leads to the activation of the effector caspases.