death receptor signals, including activation of caspase-8 and cleavage of BID, Apo2L/
TRAIL could not induce mitochondrial disruption or cell death in Bax-/- tumor cells.
These data suggest that the basal expression of BAK in tumor cells may not be
sufficient to substitute for BAX in mediating death receptor-induced apoptosis. In
addition to loss of BAX, cancer cells may also evade Apo2L/TRAIL-induced death
by overexpression of the caspase-8 inhibitor, FLIP, or upregulation of Bcl-xL (Burns
and el Deiry, 2001). As both FLIP and Bcl-xL are NF-κB-inducible proteins, this
mechanism of resistance may operate in cancers that have constitutively high NF-κB
activity (Ravi et al., 2001). Since NF-κB is frequently activated by diverse genetic
aberrations, growth factors, cytokines, viral proteins, costimulatory interactions, and
stressful stimuli in diverse cancer types, it may be a common denominator of the
resistance of many human cancers to Apo2L/TRAIL. Conversely, such cancers may
be sensitized to Apo2L/TRAIL-induced death by inhibitors of NF-κB (Ravi and Bedi,
2002). Tumor cells can also be sensitized to Apo2L/TRAIL-induced apoptosis by
various chemotherapeutic agents or ionizing radiation. Since death-receptor and
DNA damage/stress-induced pathways operate largely independently until they
converge at the level of mitochondrial disruption, the simultaneous delivery of both
signals may have synergistic cytotoxicity. Moreover, conventional chemotherapeutic
agents may also potentiate Apo2L/TRAIL-induced tumor cell death by upregulating
p53, DR5/TRAIL-R2, and BAK (LeBlanc et al., 2002). Although the combination
of Apo2L/TRAIL with either NF-κB inhibitors or conventional anticancer agents
may exert synergistic antitumor effects, additional studies are required to evaluate
and optimize the safety and therapeutic ratio of such regimens in vivo.
8.
ConclusionThe last decade has witnessed breathtaking progress in our understanding of cell death
and its fundamental physiologic importance in multicellular animals. Enormous
strides have been made in identifying the molecular assassins and the mechanisms by
which they direct cell death. As our knowledge of death receptors and their signaling
pathways has grown, so too has our appreciation of the key survival signals that keep
them in check. It is now evident that evolution has designed an intricate molecular
circuitry that maintains a dynamic balance between death receptors and antiapoptotic
proteins. The stringent regulation of death receptor-induced apoptosis enables signal-
dependent induction of physiologic cell death while protecting the organism from
the devastating consequences of unscheduled or uncontrolled apoptosis. These
insights into the molecular regulation of cell death have opened exciting avenues for
therapeutic interventions against diseases that involve too much apoptosis or the
failure of physiologic cell death. The challenge before us is to design innovative
therapeutic strategies that counteract these defects by targeting death receptors or
their regulatory pathways. Apo2L/TRAIL may prove that we have already embarked
on a journey from death receptors to successful anticancer therapy. The next decade
DEATH RECEPTORS IN APOPTOSIS 31