Although death receptors play contributory, yet dispensable, roles in the response
to conventional chemotherapy or irradiation, death receptor-ligand interactions may
be instrumental for the action of cancer immunotherapy or specific anticancer agents.
One example of how anticancer agents may employ death receptors-ligands in their
actions is all-trans-retinoic acid (ATRA), a retinoid that induces complete remissions
in approximately 10% of patients with acute promyelocytic leukemia. ATRA induces
APL-cell differentiation followed by postmaturation apoptosis through induction of
Apo2L/TRAIL (Altucci et al., 2001). ATRA-induced expression of Apo2L/TRAIL
Figure 3. Cross-talk between the death receptor (extrinsic) and stress-induced (intrinsic/
mitochondrial) death signaling pathways.
Cellular stress or DNA damage results in stabilization of p53. p53 can promote mitochondrial
activation of caspase-9/Apaf-1 by inducing the expression of specific target genes, such as Noxa,
PUMA, or Bax. The stress/DNA damage and death receptor signaling pathways operate largely
independently until they converge at the level of mitochondrial disruption. The following
mechanistic links between the intrinsic and extrinsic pathways may account for the synergistic
cytotoxicity of chemotherapeutic agents/irradiation and death ligands: (1) DNA damage
promotes expression of the death receptors (CD95 and DR5/TRAIL-R2). (2) Cellular damage
inflicted by chemotherapeutic agents can promote expression of BAK. (3) p53 may inhibit the
transcriptional activity of NF-κB.
28 GENETICS OF APOPTOSIS