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Research Paper
Doxorubicin Pretreatment Sensitizes Prostate Cancer Cell Lines to TRAIL Induced Apoptosis Which Correlates with the Loss of c-FLIP Expression
Margaret M. Kelly, Brian D. Hoel and Christina Voelkel-Johnson
volume 1 | issue 5
September/October 2002Pages: 520-527
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Tumor necrosis factor-related apoptosis inducing ligand (TRAIL/Apo2L) can induce receptor-mediated apoptosis in prostate cancer cell lines that have been co-treated with the chemotherapeutic agent doxorubicin (Voelkel-Johnson C, et al. Cancer Gene Therapy 2002; 9:164–172). In this study, we report that pretreatment with doxorubicin is sufficient to sensitize cells to TRAIL. To identify possible targets of doxorubicin, we analyzed levels of several Bcl-2 family members, TRAIL receptors and the anti-apoptotic protein c-FLIP. Doxorubicin did not affect steady state levels of Bax, Bcl-2 and Bcl-XL in the majority of the prostate cancer cell lines. TRAIL receptor mRNAs (DR4, DR5, and DcR2) were induced by doxorubicin but these changes were not reflected at the protein level. In contrast, in response to doxorubicin, levels of c-FLIP, particularly FLIPS, decreased in all cell lines tested. The decrease in c-FLIPS correlated with onset and magnitude of caspase-8 and PARP cleavage in PC3 cells. In two TRAIL resistant cell lines, DU145 and LNCaP, treatment with TRAIL alone resulted in processing of c-FLIPL and initiated abortive caspase-8 proteolysis. TRAIL treatment did not affect levels of c-FLIPS in Du145 and LNCaP cells and did not result in PARP cleavage. Therefore, our results suggest that doxorubicin- mediated down regulation of c-FLIPS predisposes cells to TRAIL-induced apoptosis.
Key Words:
TRAIL, Doxorubicin, Apoptosis, Prostate cancer, c-FLIP
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.