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Pretreatment with Paclitaxel Enhances Apo-2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis of Prostate Cancer Cells by Inducing Death Receptors 4 and 5 Protein Levels

Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612 [R. N., C. L. P., E. O., K. N. B.], and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136 [M. O., D. N.]

	ABSTRACT

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We have demonstrated that Apo-2 ligand (Apo-2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of human prostate cancer PC-3, DU145, and LNCaP cells in a dose-dependent manner, with PC-3 cells displaying the greatest sensitivity to Apo-2L/TRAIL. Susceptibility of the prostate cancer cell types to Apo-2L/TRAIL-induced apoptosis did not appear to correlate with the levels of the Apo-2L/TRAIL receptors death receptor (DR) 4 (TRAIL receptor 1) or DR5 (TRAIL receptor 2), decoy receptor (DcR) 1 and DcR2, Flame-1, or the inhibitors of apoptosis proteins family of proteins. Apo-2L/TRAIL-induced apoptosis of PC-3 cells was associated with the processing of caspase-8, caspase-10, and the proapoptotic Bid protein, resulting in the cytosolic accumulation of cytochrome c as well as the processing of procaspase-9 and procaspase-3. Cotreatment with the caspase-8 inhibitor z-IETD-fmk or DR4: Fc significantly inhibited Apo-2L/TRAIL-induced apoptosis. Treatment with paclitaxel or taxotere increased DR4 and/or DR5 protein levels (up to 8-fold) without affecting the protein levels of DcR1 and DcR2, Apo-2L/TRAIL, Fas, or Fas ligand. Up-regulation of DR4 and DR5 was not preceded by the induction of their mRNA levels but was inhibited by cotreatment with cycloheximide. Importantly, sequential treatment of PC-3, DU145, and LNCaP cells with paclitaxel followed by Apo-2L/TRAIL induced significantly more apoptosis than Apo-2L/TRAIL treatment alone (P < 0.01). This was also associated with greater processing of procaspase-8 and Bid, as well as greater cytosolic accumulation of cytochrome c and the processing of caspase-3. These findings indicate that up-regulation of DR4 and DR5 protein levels by treatment with paclitaxel enhances subsequent Apo-2L/TRAIL-induced apoptosis of human prostate cancer cells.

	INTRODUCTION

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TRAIL,² also called Apo-2L, has been shown to induce apoptosis of a variety of tumor cell types (1, 2, 3) . Apo-2L/TRAIL suppresses human mammary adenocarcinoma growth in mice without any of the significant toxic effects seen with the in vivo use of tumor necrosis factor and FasL (CD95L) (Ref. 4 ). Apo-2L/TRAIL can bind to five members of the tumor necrosis factor receptor family, i.e., DR4, DR5, DcR1, DcR2, and osteoprotegerin (1 , 2) . DR4 and DR5 contain a cytoplasmic region consisting of a stretch of 80 amino acids designated as the death domain responsible for transducing the death signal (1 , 2) . Binding of Apo-2L/TRAIL to DR4 and DR5 leads to the cleavage and activation of caspase-8 and caspase-10 (1 , 2) . These, in turn, activate downstream effector caspases such as caspase-3, caspase-6, and caspase-7 (5) . Processed and activated caspase-8 can also cleave and activate the BH3 domain containing the proapoptotic Bid protein, which then translocates to the mitochondria, triggering the cytosolic release of cyt c (6) . In the cytosol, cyt c and dATP bind to Apaf-1 and cause its oligomerization (7) . Apaf-1, in turn, binds one-to-one, oligomerizes, and processes procaspase-9 into an active caspase, which recruits, cleaves, and activates the executioner caspase-3 (7 , 8) . This can proteolytically cleave a number of cellular proteins, e.g., poly(ADP-ribose) polymerase, DNA fragmentation factor 45 [inhibitor of caspase-activated deoxyribonuclease (ICAD)], and so forth, resulting in the morphological features and DNA fragmentation of apoptosis (9) . There are several known determinants of Apo-2L/TRAIL-induced apoptotic signaling. Treatment with DNA-damaging anticancer agents can induce p53 and/or nuclear factor B, which, in turn, can up-regulate DR5 and/or DR4 expression, thereby enhancing Apo-2L/TRAIL-induced apoptotic signaling (10 , 11) . In contrast, DcR1 and DcR2 bind and titrate Apo-2L/TRAIL and can act as inhibitors of Apo-2L/TRAIL-induced apoptosis (1 , 2) . An intracellular protein, Flame-1 (also known as c-FLIP, CASH, CLARP, MRIT, and usurpin), which has an NH₂ terminus Fas-associated death domain (FADD) homology and COOH terminus caspase homology domains without caspase activity, has a dominant negative effect against caspase-8 and caspase-10 and can potentially inhibit Apo-2L/TRAIL-induced death signaling (12) . Finally, the levels of IAP family members, which include cIAP1, cIAP2, X-linked XIAP, and survivin, may also inhibit TRAIL-induced apoptosis by specifically binding to and inhibiting the activities of caspase-3, caspase-9, and caspase-7 (13) . Taxanes, such as paclitaxel and taxotere, are highly active anticancer drugs that are currently being investigated for their activities against human prostate carcinoma (14) . Taxane-induced apoptosis is triggered by mitochondrial m (permeability transition), release of cyt c into the cytosol, and induction of Apaf-1-mediated caspase-9 and caspase-3 activities (15 , 16) . In the present studies, we determined the sensitivity and molecular steps of apoptosis triggered by Apo-2L/TRAIL and/or paclitaxel in human prostate cancer cells. We demonstrate that Apo-2L/TRAIL triggers the molecular events of both the extrinsic (DR) and intrinsic (mitochondrial) pathway of apoptosis. Importantly, we also show that pretreatment with paclitaxel or taxotere induces DR4 and DR5 protein levels and enhances Apo-2L/TRAIL-induced apoptosis of prostate cancer cells.

	MATERIALS AND METHODS

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Reagents.
z-IETD-fluoromethyl ketone (fmk) and z-LEHD-fmk were purchased from Enzyme Systems Products (Livermore, CA). Anti-Apaf-1 and anti-Bid antisera (6 , 7) were kindly provided by Dr. Xiaodong Wang (University of Texas Southwestern School of Medicine, Dallas, TX). The recombinant human homotrimeric Apo-2L/TRAIL (leucine zipper construct) was a gift from Immunex Corp. (Seattle, WA; Ref. 4 ). Fas receptor (CD95) and FasL monoclonal antibodies were purchased from Transduction Laboratories (Lexington, KY). Monoclonal Anti-XIAP antibody was purchased from Boehringer Mannheim (Indianapolis, IN), whereas anti-cIAP-1 and anti-Flame-1 (IFLICE) antibodies were purchased from PharMingen (San Diego, CA). Polyclonal anti-DR4, anti-DcR1, and anti-Apo-2L/TRAIL antibodies were purchased from Alexis Corp. (San Diego, CA). Polyclonal anti-caspase-8 antibody was purchased from Upstate Biotechnology (Lake Placid, NY), and anti-DR5 was obtained from Cayman Chemicals Co. (Ann Arbor, MI). Monoclonal anti-survivin antibody was purchased from R&D Systems (Minneapolis, MN).

Cell Culture.
Prostate cancer cell lines PC-3, DU145, and LNCaP were obtained from American Type Culture Collection and maintained in a humidified 5.0% CO₂ environment in RPMI 1640 supplemented with 100 units/ml penicillin, 100 µg/ml streptomycin, 1% nonessential amino acids, 1% essential amino acids, and 10% bovine calf serum (Life Technologies, Inc., Grand Island, NY).

Western Analyses of Proteins.
Western analyses of DR4, DR5, DcR1, DcR2, Apo-2L/TRAIL, procaspase-9, caspase-10, caspase-3, Fas receptor, FasL, survivin, Bid, poly(ADP-ribose) polymerase, and ß-actin were performed using specific antisera or monoclonal antibodies according to protocols reported previously (15 , 16) . Horizontal scanning densitometry was performed on Western blots by using acquisition into Adobe Photo Shop (Apple, Inc., Cupertino, CA) and analysis by the NIH Image Program (NIH, Bethesda, MD). The expression of ß-actin was used as a control.

RNase Protection Assay.
A RiboQuant Multi-Probe RNase Protection Assay System was used according to the manufacturer’s instructions (PharMingen). A hAPO3c probe set including the DNA templates for caspase-8, FasL, Fas, DcR1, DR4, DR5, receptor-interacting protein (RIP), L32, glyceraldehyde-3-phosphate dehydrogenase, and so forth was used for T7 RNA polymerase-directed synthesis of [³²P]UTP-labeled antisense RNA probes. The probes were hybridized with 20 µg of RNA isolated from prostate cancer cells (PC-3) after treatment with Taxol at different time points using RNazol B. Samples were then digested with RNase to remove single-stranded (nonhybridized) RNA. The remaining probes were resolved on denaturing 5% polyacrylamide gels.

Preparation of the S-100 Fraction for the Analysis of Cytosolic Accumulation of Cyt c.
Untreated and drug-treated cells were harvested by centrifugation, and the cell homogenates were centrifuged at 100,000 x g for 30 min at 4°C to obtain the S-100 fraction, as described previously (15 , 16) . The supernatants were collected, and the protein concentrations of S-100 were determined by the Bradford method (Bio-Rad, Hercules, CA). Samples were then analyzed for the release of cyt c from the mitochondria into the cytosol by Western blot, as described previously (15 , 16) .

Flow Cytometric Analysis of Sub-G₁ (Hypodiploid) Apoptotic Cells.
The flow cytometric evaluation of PI-stained apoptotic cells was performed according to a method described previously (17) . The percentage of sub-G₁ (hypodiploid) apoptotic cells was calculated using Multicycle software (Phoenix Flow Systems, San Diego, CA).

Apoptosis Assessment by Annexin V Staining.
After drug treatment, cells were resuspended in 100 µl of staining solution (containing annexin V fluorescein and PI in a HEPES buffer; Annexin-V-FLUOS Staining Kit; Boehringer Mannheim). After incubation at room temperature for 15 min, cells were analyzed by flow cytometry. Annexin V binds to cells that express phosphatidylserine on the outer layer of the cell membrane, and PI stains the cellular DNA of cells with a compromised cell membrane. This allows for the discrimination of live cells (unstained with either fluorochrome) from apoptotic cells (stained only with annexin V) and necrotic cells (stained with both annexin V and PI; Ref. 17 ).

Statistical Analysis.
Significant differences between values obtained in a population of leukemic cells treated with different experimental conditions were determined by paired t test analyses. A one-way ANOVA was also applied to the results of the various treatment groups, and post hoc analysis was performed using the Bonferroni correction method.

	RESULTS AND DISCUSSION

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Apo-2L/TRAIL Induces Apoptosis of Human Prostate Cancer Cells.
Apo-2L/TRAIL has been reported to induce apoptosis of a variety of tumor cell types (3 , 4) . However, the molecular determinants of Apo-2L/TRAIL-induced apoptosis had not been comprehensively examined in human prostate cancer cells. Fig. 1A demonstrates that exposure of human prostate cancer PC-3 cells to 100–250 ng/ml Apo-2L/TRAIL for 24 h caused a dose-dependent increase in the percentage of apoptotic cells, as determined by annexin V staining followed by flow cytometry. This was confirmed by light microscopic morphological examination of Wright-stained, cytospun, Apo-2L/TRAIL-treated PC-3 cells (data not shown). Apo-2L/TRAIL was less active against DU145 and LNCaP cells. For example, exposure to 100 ng/ml Apo-2L/TRAIL for 24 h induced apoptosis of 11.6 ± 2.5% of DU145 and 7.6 ± 1.2% of LNCaP cells, as compared with 39.8 ± 1.2% of PC-3 cells (mean ± SE of three experiments). Previous reports have suggested that the sensitivity to Apo-2L/TRAIL-induced apoptosis can be correlated to the relative expressions of DR4 and DR5 versus DcR1 and DcR2 or the intracellular levels of Flame-1 (2 , 3) . Fig. 1D demonstrates that, as compared with LNCaP cells, which have the lowest sensitivity to Apo-2L/TRAIL-induced apoptosis, highly sensitive PC-3 cells displayed similar or lower protein levels of DR4 and DR5 and higher levels of DcR2. DcR1 expression was barely detectable in all cell types. Counterintuitively, Flame-1 and XIAP levels were also higher in PC-3 cells than in LNCaP cells. Fig. 1D also shows that PC-3 cells display a lower Bax:Bcl-2 expression ratio as compared with the relatively resistant LNCaP cells. Although the data are not shown, survivin levels were also not significantly different between PC-3 and LNCaP cells (13) . The expression levels of these regulators of apoptosis also did not offer a clear explanation for the intermediate sensitivity to Apo-2L/TRAIL-induced apoptosis of DU145 cells. The lack of correlation between the expression of DRs (DR4 and DR5) and DcRs (DcR1 and DcR2) or Flame-1 with the sensitivity to Apo-2L/TRAIL-induced apoptosis shown by our findings differs from some but not all previously reported findings (3 , 11 , 18, 19, 20) . This may be because our data are derived from prostate cancer cells, unlike other reports in which other cell types were studied.

View larger version (44K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Apo-2L/TRAIL- or paclitaxel (Taxol)-induced apoptosis and the levels of its molecular regulators in prostate cancer cells. PC-3 cells were exposed to 10, 100, or 250 ng/ml Apo-2L/TRAIL or 20, 100, or 250 nM paclitaxel for 24 h. Immediately after Apo-2L/TRAIL exposure (A) or 24 h after paclitaxel exposure (B), cells were stained with annexin V, and the percentage of positively stained apoptotic cells was determined by flow cytometry (see "Materials and Methods"). Alternatively, after exposure of PC-3 cells to Taxol (100 nM), Apo-2L/TRAIL (100 ng/ml), z-IETD-fmk (50 µg/ml), or Apo-2L/TRAIL R1:Fc (10 ng/ml) alone or treatment with a combination of Taxol plus z-IETD-fmk, Taxol plus Apo-2L/TRAIL R1:Fc, Apo-2L/TRAIL plus z-IETD-fmk, or Apo-2L/TRAIL plus Apo-2L/TRAIL R1:Fc, the percentage of apoptotic PC-3 cells positively stained with annexin V was determined by flow cytometry (C). A representative immunoblot analysis using specific antibodies is presented showing the levels of the designated proteins (D; see "Materials and Methods").

Recent reports have demonstrated that DNA-damaging agents such as etoposide, doxorubicin, CPT-11, and ionizing radiation can augment Apo-2L/TRAIL-induced apoptosis of breast cancer cells, perhaps by inducing p53 and/or nuclear factor B activity and DR5 and/or DR4 expression (10 , 11 , 18, 19, 20, 21, 22) . In the present studies, we determined the effect of antimicrotubule taxanes on DR4 and DR5 expression and Apo-2L/TRAIL-induced apoptosis of prostate cancer cells. Fig. 2A demonstrates that treatment with clinically relevant concentrations of paclitaxel (500 nM) or taxotere (100 nM) increases DR4 and DR5 protein levels in a time-dependent manner; maximal enhancement was observed within 12 h of exposure to the drugs (Fig. 2A) . Exposure to paclitaxel (Fig. 2B) and taxotere (data not shown) also increased DR4 and DR5 levels in a dose-dependent manner. It should be noted that PC-3 cells are known to have a mutant p53 and display an absence of p53 nuclear immunostaining (23) . Although wild-type p53 can induce DR5, a previous report has also suggested that DR4 or DR5 expression and its induction are not affected by a compromised p53 function (20) . Fig. 2C shows the results of a representative RiboQuant Multi-Probe RNase Protection Assay demonstrating that treatment of PC-3 cells with paclitaxel did not induce the mRNA level of Apo-2L/TRAIL, DR4, DR5, Fas, or caspase-8. This suggested that the induction of DR4 and DR5 levels by paclitaxel may be posttranscriptional. Whereas exposure to paclitaxel also increased DR4 and DR5 levels, in DU145 and LNCaP cells, this effect was decreased when compared with that seen in PC-3 cells (Fig. 2D) . Findings shown in Fig. 2E demonstrate that whereas cotreatment with actinomycin D (500 ng/ml) had no effect, cotreatment with cycloheximide (100 µg/ml) reduced paclitaxel-mediated DR4 and, to a lesser extent, DR5 induction in PC-3 cells. However, our studies did not address the mechanism of posttranscriptional induction of DR4 or DR5 by paclitaxel.

View larger version (71K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Treatment of PC-3 cells with taxanes paclitaxel (Taxol) and taxotere increases the protein but not the mRNA levels of DR4 and DR5. PC-3 cells were treated with 500 nM paclitaxel or 100 nM taxotere for the indicated time intervals (A) or exposed to 20, 100, or 500 nM paclitaxel for 24 h (B). After these treatments, immunoblot analyses of the levels of the indicated proteins were performed using specific antibodies (see "Materials and Methods"). After exposure to 100 nM paclitaxel for the indicated time intervals (indicated in hours), mRNA expression levels of the indicated genes were also determined using a Riboquant Multi-Probe RNase Protection Assay (C; see "Materials and Methods"). DU145 or LNCaP cells were exposed to 100 nM Taxol, and immunoblot analyses of DR4 and DR5 expression were performed (D). Alternatively, PC-3 cells were treated with Taxol (100 nM), actinomycin D (500 ng/ml), or cycloheximide (100 µg/ml) alone for 24 h or with combinations of Taxol plus actinomycin D or Taxol plus cycloheximide for 24 h. After these treatments, immunoblot analysis of DR4 and DR5 protein levels was performed, with ß-actin serving as the loading control (E; see "Materials and Methods").

View larger version (45K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Pretreatment with paclitaxel increases Apo-2L/TRAIL-induced apoptosis of prostate cancer cells. A, PC-3 cells were exposed to Taxol (500 nM) or Apo-2L/TRAIL (100 ng/ml) alone for 24 h. Alternatively, cells were treated with Taxol for 24 h followed by Apo-2L/TRAIL for 24 h or with a reversed sequence of the treatments or a concurrent treatment with Taxol plus Apo-2L/TRAIL. After these treatments, the percentage of annexin V-stained apoptotic cells was determined. The bar graphs values represent the means ± SE of three experiments. B, DU145 and LNCaP cells were exposed to Taxol (100 nM) or Apo-2L/TRAIL (100 ng/ml) alone for 24 h. Alternatively, cells were treated with Taxol for 24 h followed by Apo-2L/TRAIL for 24 h or with a reversed sequence of the treatments. After these treatments, the percentage of annexin V- and PI-stained cells was determined. The values represent the mean of three independent experiments ± SD.

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Pretreatment with paclitaxel up-regulates DR4 and DR5 expression and enhances Apo-2L/TRAIL-induced caspase-8, caspase-10, and Bid processing and the cytosolic accumulation of cyt c. PC-3 cells were exposed to Taxol (100 nM) or Apo-2L/TRAIL (100 ng/ml) alone for 24 h or treated with Taxol for 24 h followed by Apo-2L/TRAIL for 24 h. After these treatments, immunoblot analyses of the indicated proteins were performed using specific antibodies (see "Materials and Methods").

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, MRC 3 East, Room 3056 Tampa, FL 33612. Phone: (813) 903-6861; Fax: (813) 903-6817; E-mail: bhallakn{at}moffitt.usf.edu

² The abbreviations used are: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; Apo-2L, Apo-2 ligand; DR, death receptor; DcR, decoy receptor; IAP, inhibitors of apoptosis proteins; cyt c, cytochrome c; R1, receptor 1; FasL, Fas ligand; PI, propidium iodide.

Received 6/28/00. Accepted 11/14/00.

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