Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2-or Bcl-x(L)-overexpressing chemotherapy-resistant tumor cells

Citation
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
Citations number
50
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
60
Issue
11
Year of publication
2000
Pages
3051 - 3057
Database
ISI
SICI code
0008-5472(20000601)60:11<3051:TNFALR>2.0.ZU;2-F
Abstract
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.