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Tumor Biology |
Departments of Medicine [X. Y. L., Mi. M., B. K., F. A., Ma. M.] and Molecular and Cellular Biology [Ma. M.], Baylor College of Medicine; Veterans Affairs Medical Center [X. Y. L., Mi. M., B. K., Ma. M.], Houston, Texas 77030; Institute of Internal Medicine and Oncologic Sciences, Perugia University Medical School, I-06100 Perugia, Italy [R. M., I. N.]; and Department of Molecular and Cellular Biology, Texas Biotechnology Corporation, Houston, Texas 77030 [L. D.]
We have reported previously that among human prostate cancer cell lines LNCaP but not PC-3 cells undergo apoptosis after treatment with the protein kinase inhibitor staurosporine (STS). We have now further investigated this model to uncover the molecular mechanism causing resistance to STS-induced apoptosis in PC-3 cells. S-100 lysates of both cell lines showed biochemical changes typical of apoptosis after the addition of cytochrome c and dATP, suggesting that the postmitochondrial phase of apoptosis was intact. Upon addition of STS, the proapoptotic molecules Bax and Bad became predominantly mitochondrial in both cell lines. This, in turn, was followed by loss of mitochondrial transmembrane potential, translocation of cytochrome c to the cytosol, activation of caspase-9, -3, and -7, and cleavage of the apoptotic targets, DNA fragmentation factor and poly(ADP-ribose) polymerase, in LNCaP but not in PC-3 cells. Components of the mitochondrial permeability transition pore, adenine nucleotide transporter and voltage-dependent anion channel, were normally expressed in the correct subcellular fraction of both cell lines. Overexpression of the proapoptotic proteins Bax and Bad, fused to a green fluorescent protein but not of green fluorescent protein alone, induced apoptosis in >80% of PC-3 cells. These experiments suggested that a factor protecting the mitochondria of PC-3 cells mediates resistance to STS-induced apoptosis. A wide search among the antiapoptotic Bcl-2 family members was performed, and Bcl-XL was found to be overexpresseÃd in PC-3 cells. Experiments down-regulating Bcl-XL expression by using the tyrosine kinase inhibitor genistein, sodium butyrate, or an antisense Bcl-XL oligonucleotide restored sensitivity to apoptosis in PC-3 cells. Thus, Bcl-XL overexpression is one of the mediators of resistance to STS-induced apoptosis in the prostate cancer cell line PC-3.
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