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Department of Oncology and Immunology, Newcastle, New South Wales, Australia
Past studies have shown that TNF-related apoptosis-inducing ligand
(TRAIL) induced apoptosis in a high proportion of cultured melanoma by
caspase-dependent mechanisms. In the present studies we have examined
whether TRAIL-induced apoptosis of melanoma was mediated by direct
activation of effector caspases or whether apoptosis was dependent on
changes in mitochondrial membrane potential (MMP) and
mitochondrial-dependent pathways of apoptosis. Changes in MMP were
measured by fluorescent emission from rhodamine 123 in mitochondria.
TRAIL, but not TNF-
or Fas ligand, was shown to induce marked
changes in MMP in melanoma, which showed a high correlation with
TRAIL-induced apoptosis. This was associated with activation of
proapoptotic protein Bid and release of cytochrome c
into the cytosol. Overexpression of B cell lymphoma gene 2
(Bcl-2) inhibited TRAIL-induced release of cytochrome
c, changes in MMP, and apoptosis. The pan caspase
inhibitor z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) and the inhibitor
of caspase-8 (z-Ile-Glu-Thr-Asp-fluoromethylketone; zIETD-fmk) blocked
changes in MMP and apoptosis, suggesting that the changes in MMP were
dependent on activation of caspase-8. Activation of caspase-9 also
appeared necessary for TRAIL-induced apoptosis of melanoma. In
addition, TRAIL, but not TNF- or Fas ligand, was shown to induce
clustering of mitochondria around the nucleus. This process was not
essential for apoptosis but appeared to increase the rate of apoptosis.
Taken together, these results suggest that TRAIL induces apoptosis of
melanoma cells by recruitment of mitochondrial pathways to apoptosis
that are dependent on activation of caspase-8. Therefore, factors that
regulate the mitochondrial pathway may be important determinants of
TRAIL-induced apoptosis of melanoma.
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