H. Walczak et al., Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2-or Bcl-x(L)-overexpressing chemotherapy-resistant tumor cells, CANCER RES, 60(11), 2000, pp. 3051-3057
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member
of the tumor necrosis factor family and has recently been shown to exert t
umoricidal activity in vivo in the absence of any observable toxicity. The
signaling pathways triggered by TRAIL stimulation and the mechanisms involv
ed in resistance against TRAIL-mediated apoptosis are still poorly defined.
We show here that TRAIL-induced apoptosis involves late dissipation of mit
ochondrial membrane potential (Delta Psi(m)) and cytochrome c release. Thes
e events follow activation of caspase-8 and caspase-3 and induction of DNA
fragmentation. In addition, caspase-8-deficient cells are resistant against
TRAIL-induced apoptosis, and inhibition of caspase-8 but not caspase-9 pre
vents mitochondrial permeability transition and apoptosis, In contrast, var
ious Bcl-2- or Bcl-x(L)-overexpressing tumor cell lines are sensitive to TR
AIL-induced apoptosis; however, they show a delay in TRAIL-induced mitochon
drial permeability transition compared with control transfectants. This ind
icates that TRAIL-induced apoptosis depends on caspase-8 activation rather
than on the disruption of mitochondrial integrity. Because most chemotherap
eutic drugs used in the treatment of malignancies lead to apoptosis primari
ly by engagement of the mitochondrial proapoptotic machinery, we tested whe
ther drug-resistant tumor cells retain sensitivity for TRAIL-induced apopto
sis, Tumor cells overexpressing Bcl-2 or Bcl-x(L) become resistant to apopt
osis induced by the chemotherapeutic drug etoposide, However, these cells a
re not protected or are only marginally protected against TRAIL-induced apo
ptosis, Thus, TRAIL may still kill tumors that have acquired resistance to
chemotherapeutic drugs by overexpression of Bcl-2 or Bcl-x(L). These data w
ill influence future treatment strategies involving TRAIL.