tumors by NK cells. Expression of FasL on cells other than NK cells might also
contribute to tumor suppression (Owen-Schaub et al., 1998).
7.2
Involvement of death receptors in response of tumor cells to
anticancer therapyThe response of cancer cells to chemotherapeutic agents and γ-radiation involves
induction of apoptosis in response to the inflicted cellular damage (Rich et al., 2000).
The ability of anticancer agents to induce tumor-cell apoptosis is influenced by a host
of oncogenes and tumor suppressor genes that regulate cell-cycle checkpoints and
death-signaling pathways. The p53 tumor suppressor gene is a key determinant of
these responses (el Deiry, 1998; Kirsch and Kastan, 1998). Phosphorylation-induced
stabilization of p53 in response to cellular damage plays a pivotal role in mediating
cell-cycle arrest as well as apoptosis. The particular response elicited by p53 depends
on the cell type and context, as well as the presence of coexisting genetic aberrations.
The induction of apoptosis by p53 involves multiple and apparently redundant
mechanisms (Schuler and Green, 2001). p53 can directly activate the mitochondrial
death pathway by inducing the expression of specific target genes, such as Noxa (Oda
et al., 2000), PUMA (Nakano and Vousden, 2001), or Bax (Miyashita and Reed,
1995). p53 may also promote cell death by inhibiting the transcriptional activity of
NF-κB (Ravi et al., 1998b; Wadgaonkar et al., 1999; Webster and Perkins, 1999),
thereby repressing NF-κB-dependent expression of a host of survival genes. These
observations indicate that p53-induced death is mediated by multiple redundant
pathways leading to mitochondrial activation of Apaf-1/caspase-9. In support of this
notion, cells from caspase-9-/- mice are highly resistant to chemotherapeutic drugs
and irradiation (Kuida et al., 1998). Accordingly, inhibition of this mitochondrial
pathway by overexpression of Bcl-2 (Strasser et al., 1994) or inactivation of Bax
(Zhang, L. et al., 2000) can also render tumor cells resistant to anticancer drugs or
γ-radiation.
DNA damage also promotes the expression of the death receptors, CD95 (Muller
et al., 1998) and DR5/TRAIL-R2 (Wu, G.S. et al., 1997). Although p53 promotes
their DNA damage-induced expression, death receptors are not essential for DNA
damage-induced apoptosis. Cells from CD95-deficient (lpr), CD95L-defi-cient (gld),
FADD-/-, or caspase-8-/- mice are resistant to death receptor-induced signals, but
remain sensitive to chemotherapy and irradiation-induced apoptosis (Eischen et al.,
1997; Fuchs et al., 1997; Newton and Strasser, 2000). Likewise, overexpression of
FLIP prevents tumor-cell apoptosis by death receptors, but not by chemotherapeutic
agents or γ-radiation (Kataoka et al., 1998). Conversely, cells from p53-/- mice resist
DNA damage-induced apoptosis, but remain normally susceptible to CD95-induced
death, and p53-deficient tumor cells can be killed with CD95L or Apo2L/TRAIL
(Fuchs et al., 1997; Ravi et al., 2001). These findings indicate that the death receptor
and DNA damage/stress-induced signaling pathways operate largely independently
until they converge at the level of mitochondrial disruption (Figure 3).
DEATH RECEPTORS IN APOPTOSIS 27