Overexpression of BCL2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells.
The tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL or Apo2L) and its receptors are members of the tumor necrosis factor superfamily. TRAIL triggers apoptosis by binding to its two proapoptotic receptors DR4 and DR5, a process which is negatively regulated by binding of TRAIL to its two decoy receptors TRID and TRUNDD. Here, we show that TRAIL effectively induces apoptosis in H460 human non-small-cell lung carcinoma cells via cleavage of caspases 8, 9, 7, 3, and BID, release of cytochrome c from the mitochondria, and cleavage of poly (ADP-ribose) polymerase (PARP). However, overexpression of Bcl2 blocked TRAIL-induced apoptosis in H460 cells, which correlated with the Bcl2 protein levels. Importantly, the release of cytochrome c and cleavage of caspase 7 triggered by TRAIL were considerably blocked in Bcl2 overexpressing cells as compared to vector control cells. Moreover, inhibition of TRAIL-mediated cytochrome c release and caspase 7 activation by Bcl2 correlated with the inability of PARP to be cleaved and the inability of the Bcl2 transfectants to undergo apoptosis. Thus, these results suggest that Bcl2 can serve an anti-apoptotic function during TRAIL-dependent apoptosis by inhibiting the release of cytochrome c and activation of caspase 7, thereby blocking caspase 7-dependent cleavage of cellular substrates.
Sun
S Y
SY
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Yue
P
P
Zhou
J Y
JY
Wang
Y
Y
Choi Kim
H R
HR
Lotan
R
R
Wu
G S
GS
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D003574:Cytochrome c Group; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D011065:Poly(ADP-ribose) Polymerases; C505520:CASP7 protein, human; D053179:Caspase 7; D020169:Caspases