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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Cancer Biol Ther. Author manuscript; available in PMC Oct 6, 2006.
Published in final edited form as:
Published online Jul 6, 2005.
PMCID: PMC1592469
NIHMSID: NIHMS3414

Proteasome Inhibitors-Mediated TRAIL Resensitization and Bik Accumulation

Abstract

Proteasome inhibitors can resensitize cells that are resistant to tumors necrosis factor-related apoptotic-inducing ligand (TRAIL)-mediated apoptosis. However, the underlying mechanisms of this effect are unclear. To characterize the mechanisms of interaction between proteasome inhibitors and TRAIL protein, we evaluated the effects of combined treatment with the proteasome inhibitors bortezomib and MG132 and TRAIL protein on two TRAIL-resistant human colon cancer cell lines, DLD1-TRAIL/R and LOVO-TRAIL/R. Both bortezomib and MG132 in combination with TRAIL enhanced apoptotosis induction in these cells, as evidenced by enhanced cleavage of caspases 8, 9, and 3, Bid, poly (ADP-ribose) polymerase and by the release of cytochrome C and Smac. Subsequent studies showed that combined treatment with bortezomib or MG132 resulted in an increase of death receptor (DR) 5 and Bik at protein levels but had no effects on protein levels of DR4, Bax, Bak, Bcl-2, Bcl-XL, or Flice-inhibitory protein (FLIP). Moreover, c-Jun N-terminal kinase (JNK) is activated by these proteasome inhibitors. Blocking JNK activation with the JNK inhibitor SP600125 attenuated DR5 increase, but enhancement of apoptosis induction and increase of Bik protein were not affected. However, bortezomib-mediated TRAIL sensitization was partially blocked by using siRNA to knockdown Bik. Thus, our data suggests that accumulation of Bik may be critical for proteasome inhibitor-mediated re-sensitization of TRAIL.

Keywords: Proteasome inhibitor, bortezomib, PS-341, tumor necrosis factor-related apoptotic-inducing ligand (TRAIL), resistance, death receptor 5, Bik

Introduction

Various studies have demonstrated that some cancer cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); a potential new antitumor agent 13. Fortunately, a growing body of evidence has shown that combining TRAIL with conventional chemotherapy or other agents can lead to enhanced apoptosis induction in TRAIL-resistant cancer cells. For example, some chemotherapeutic agents e.g., 5-fluorouracil, mitomycin, cisplatin, apoptotic genes e.g., Bax, p53, siRNA for antiapoptotic genes e.g., Bcl-2, XIAP, survivin etc, XIAP antagonists, and proteasome inhibitors have been shown to be able to overcome the cells’ resistance to TRAIL 47.

However, the underlying mechanisms of the resensitization of TRAIL-induced apoptosis by some proteasome inhibitors, such as calpain inhibitor I, remain unclear 7. Moreover, several recent studies have demonstrated that proteasome inhibitors can overcome resistance to TRAIL in cancer cells of blood, colon, prostate, and bladder origin by different mechanisms, including upregulation of death receptor (DR) 4 and DR5, downregulation of Flice inhibitory protein (FLIP), and inhibition of NFκB activation 811.

We recently found that PS-341 and other proteasome inhibitors induced marked accumulations of Bik, a proapoptotic Bcl2 family member, in cancer cells and in normal cells that correlate with apoptosis induction by proteasome inhibitors in those cells 12. PS-341 mediated Bik accumulation is independent of p53 status and NFκB activity. Because PS-341 (bortezomib) was recently approved by the United States Food and Drug Administration for cancer therapy 13, we therefore further investigate the mechanisms of interaction between proteasome inhibitors and TRAIL in TRAIL-resistant cells. We evaluated two proteasome inhibitors, bortezomib 14 and MG132 15, in colon cancer cell lines DLD1-TRAIL/R and LOVO-TRAIL/R and found that both inhibitors resensitized TRAIL-resistant cells to TRAIL. Our results also suggested that proteasome inhibitor-mediated-enhanced-apoptosis induction by TRAIL is due to upregulation of Bik rather than of DR5. This finding may increase our understanding of the interaction between proteasome inhibitors and TRAIL.

MATERIALS AND METHODS

Cells and Cell Culture

DLD1-TRAIL/R and LOVO-TRAIL/R cells were selected from parental TRAIL-sensitive cells by repeated exposure to Ad/gTRAIL or TRAIL protein as reported previously 3. They were maintained in RPMI 1640 or Dulbecco’s modified Eagle’s medium supplemented with 10% (v/v) heat-inactivated fetal bovine serum, 1% glutamine, and 1X antibiotic-antimycotic mixture (Invitrogen, Carlsbad, CA, USA). All cells were cultured at 37°C in a humidified incubator containing 5% CO2.

Chemicals

Bortezomib was obtained from The University of Texas M.D. Anderson Cancer Center’s pharmacy and dissolved in phosphate-buffered saline (PBS) as a 5 mM stock solution. MG132, calpain inhibitor I (ALLN), and the JNK inhibitor SP600125 were purchased from Calbiochem (La Jolla, CA, USA) and were diluted in DMSO (Sigma, St. Louis, MO, USA) at the stock concentrations of 10 mM, 20mM, and 20 mM, respectively. Bik siRNA targeting 5′-AAGACCCCUCUCCAGAGACAU-3′, and Luciferase siRNA targrting 5′-CGUACGCGGAAUACUUCGA -3′ were synthesized by Dharmacon (Dallas, TX) and were dissolved in DEPC-treated water to 100 μM as stock solution. Transfection of siRNA was performed using Oligofectamine (Invitrogen) according to the manufacturer’s instruction.

Cell Viability Assay

Cell viability was determined using an XTT assay (Cell Proliferation Kit II; Roche Molecular Biochemicals, Indianapolis, IN, USA) as described previously16. Each experiment was performed in quadruplicate and repeated at least twice.

Western Blot Analysis

Cells were lysed in Laemmli buffer after desired treatment. Equal amounts of lysate were separated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and evaluated by Western blot analysis as described previously 3,16. Rabbit anti-human caspase-9, caspase-3, Bik/NBK, BAX, BCL-XL/s, and goat anti-human Bak antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Rabbit anti-human caspase-8 and mouse anti-human PARP antibodies, XIAP, cytochrome C, and COX4 were bought from BD Pharmingen (San Diego, CA, USA). Rabbit anti-human DR5 was obtained from R&D Systems (Minneapolis, MN, USA). Mouse anti-human DR4 was purchased from Alexis (San Diego, CA, USA), and rabbit anti-human survivin, phosphor-JNK and non-phosphor-JNK were obtained from Cell Signaling Technology (Beverly, MA, USA). Mouse anti-human β-actin was obtained from Sigma.

Cytosol Extraction

Cells were trypsinized and collected into Eppendorf tubes. After being washed once with PBS, cells were re-suspended with 100 μl of digitonin buffer (0.02% digitonin, 5-mM EDTA, 1-mM PMSF, 75-mM sucrose, 25-mM NaCl, 2.5-mM piperazine-N, N-bis [2-ethanesul-folic acid], and 0.75-mM MgCl2.6H2O) and incubated on ice for 10 min. Then they were spun in a centrifuge at 10000 rpm for 25 min. The supernatants were collected as cytosol components. Mitochondria were extracted as described previously and was used as a control16 .

Flow Cytometry Assay

Cells were trypsinized and washed once with cold PBS before being fixed with cold 70% ethanol and kept overnight at 4°C. Thirty minutes before the assay, propidium iodide staining was performed as described previously 3,16. Flow cytometry assay was performed in the Core Laboratory at M.D. Anderson Cancer Center.

Statistical Analysis

Differences between the treatment groups were assessed using an unpaired Student’s t-test and a significance level of P < 0.05.

Results

Proteasome Inhibitors Resensitized TRAIL-Resistant Cells to Recombinant TRAIL Protein

To determine the interaction between TRAIL and the proteasome inhibitors bortezomib and MG132, we pretreated the TRAIL-resistant colon cancer cell line DLD1-TRAIL/R with various concentrations of bortezomib (0.5–5 μM) and MG132 (5–20 μM) for 2 h. followed by 20 ng/ml of TRAIL protein for another 4 h. Cell viability was then determined by using an XTT assay. We found that combining TRAIL protein and these proteasome inhibitors significantly decreased cell viability, whereas TRAIL protein or each proteasome inhibitor alone had minimal effect at that same time Interval (P < 0.01, Fig. 1A). We also determined apoptosis induction by fluorescence-activated cell sorting (FACS) analysis of the Sub-G1 population and found that the combining TRAIL protein and these proteasome inhibitors dramatically increased the proportion of cells in the Sub-G1 phase (P < 0.01, Fig. 1B).

FIG. 1FIG. 1FIG. 1
Combined effects of proteasome inhibitors and TRAIL protein in TRAIL-resistant DLD1-TRAIL/R cells. DLD1-TRAIL/R cells were treated with bortezomib or MG132 for 2 h, followed by 20 ng/ml of TRAIL protein for 4 h. (A) Cell viability was determined by XTT ...

Because proteasome inhibitors themselves could kill the cancer cells after prolonged exposure 13,17, we evaluated whether a combination of proteasome inhibitors and TRAIL protein enhanced cell killing after prolonged incubation. We determined cell viability 24 h after the addition of TRAIL proteins as described above. The results showed that combined proteasome inhibitors and TRAIL protein had a more dramatic cell killing effect than did proteasome inhibitors used alone (P < 0.05, Fig. 1C) in DLD-TRAIL/R cells, suggesting that this combination treatment provides a therapeutic advantage. A similar result was observed in LOVO-TRAIL/R cells (Fig. 2A): TRAIL protein alone did not kill LOVO-TRAIL/R cells, but combination of TRAIL and the proteasome inhibitors did (P < 0.05).

FIG. 2
Combined effect of proteasome inhibitors and TRAIL protein in TRAIL-resistant LOVO-TRAIL/R cells. LOVO-TRAIL/R cells were treated with bortezomib or MG132 for 2 h, followed by 20 ng/ml of TRAIL protein for 24 h. Cell viability was then determined by XTT ...

The Combination of Proteasome Inhibitors and TRAIL Amplified Apoptotic Signaling

To further document the combined effects of proteasome inhibitors and TRAIL protein we analyzed the cleavage of several molecular markers of TRAIL-induced apoptotic signaling, including caspases8, 9, and 3, Bid, and poly (ADP-ribose) polymerase (PARP) by Western blotting. DLD1-TRAIL/R cells were pretreated with bortezomib (1 μM) or MG132 (5 μM) for 2 h, followed by 20 ng/ml of TRAIL protein for another 4 h. Cell lysates were then harvested and subjected to Western blot analysis. We found that the combination of TRAIL protein and proteasome inhibitors dramatically enhanced the cleavage of all those molecules, Whereas TRAIL protein or the two proteasome inhibitors alone induced only minimal changes (Fig. 3A). We also found that the combination treatment increased the release of cytochrome C and Smac from mitochondria (Fig. 3B). It was interesting that the proteasome inhibitors alone also induced a detectable release of cytochrome C.

FIG. 3FIG. 3FIG. 3
Apoptosis profiles of DLD1-TRAIL/R cells treated with bortezomib (1 μM) or MG132 (5 μM) for 2 h, followed by 20 ng/ml of TRAIL protein for 4 h. Cell lysates were then subjected to Western blot analysis. (A) cleavage of caspases. (B) Release ...

A similar result was observed when cell lysates were harvested 24 h after the addition of TRAIL protein (Fig. 3C), although by that time, the single agent-induced changes had also increased from their levels at 4 h. Specifically, clear cleavage of caspases9 and 3 and PARP but not caspase 8 was observed after treatment with proteasome inhibitors alone (Fig. 3C), suggesting that proteasome inhibitors initiate mainly the mitochondrial apoptotic pathway.

Proteasome Inhibitors Upregulated DR5 and Bik

To characterize the mechanisms of interaction between proteasome inhibitors and TRAIL protein, we analyzed changes in the DRs including DR4 and DR5, and in Bcl-2 family members such as Bax, Bak, Bik, Bcl-2, and Bcl-XL, which are important for initiation of the mitochondrial pathway 18,19. To determine the changes in these molecules after combination therapy, we treated DLD1-TRAIL/R cells with bortezomib (1 μM) or MG132 (5 μM) for 2 h, followed by 20 ng/ml of TRAIL protein for 4 h. Cell lysates were then collected for Western blot analysis. In accord with the results reported in other studies 9,20, we found that both bortezomib and MG132 mildly upregulated DR5 in DLD1-TRAIL/R cells (Fig. 4). Both proteasome inhibitors dramatically upregulated Bik protein, an initiator of the mitochondrial apoptotic pathway 21; however, they had no detectable effects on DR4, Bax, Bak, Bcl-2, or Bcl-XL (Fig. 4). Neither proteasome inhibitors alone nor the combination therapy had any detectable effects on other antiapoptotic proteins, such as XIAP, survivin (Fig. 4), and FLIP (data not shown).

FIG. 4
DR5 and Bik upregulation by proteasome inhibitors. DLD1-TRAIL/R TRAIL-resistant cells treated with bortezomib (1 μM) or MG132 (5 μM) for 2 h followed by 20 ng/ml of TRAIL protein for 4 h. The cell lysates were then subjected to Western ...

Activation of c-Jun N-terminal Kinase (JNK) by Proteasome Inhibitors Is Possibly Correlated with Upregulation of DR5 but Not Apoptosis

It has been reported that proteasome inhibitors induce apoptosis by activating JNK pathway 22. To determine whether JNK activation played a role in the enhanced cell killing observed in DLD1-TRAIL/R cells, we evaluated JNK activation after treatment with TRAIL, proteasome inhibitors, or both. We found that both bortezomib and MG132 induced phosphor-JNK kinases, suggesting that these proteasome inhibitors can activate the JNK pathway (Fig. 5A).

FIG. 5FIG. 5FIG. 5FIG. 5
JNK pathway activation by proteasome inhibitors. (A). JNK activation detected in TRAIL-resistant DLD1-TRAIL/R cells treated as described in the Fig. 4. The data presented are from one of two independent experiments with similar results. (B) Effect of ...

To test whether JNK activation is critical in the enhanced apoptosis induction observed with the combination therapy, we added the JNK inhibitor SP600125 23 to the treatment. Addition of SP600125 partially attenuated the proteasome inhibitor-induced phosphor-JNK (Fig. 5B) and reduced the level of proteasome inhibitor-induced DR5 but not of Bik (Fig. 5B). However, FACS analysis showed that addition of the JNK inhibitor did not block the apoptosis induced by the combination treatment (P > 0.05, Fig. 5C). These data demonstrated that proteasome inhibitor-induced activation of the JNK pathway and upregulation of DR5 are not the major contributors to the enhanced level of apoptosis induced by combination treatment.

Knockdown of Bik by siRNA diminished TRAIL sensitization by proteasome inhibitors

We then tested effects of proteasome inhibitor-mediated Bik accumulation on TRAIL sensitization. For this purpose, we used Bik siRNA to knockdown Bik accumulation. Our previous result showed that the Bik specific siRNA can block about 50% of Bik expression and 50% of Bik accumulation after treatment bortezomib12. In comparison with control siRNA, treatment with Bik siRNA significantly attenuated bortezomib-mediated TRAIL sensitization (P <0.05, Fig. 5D). This result suggested that bortezomib-mediated Bik accumulation plays an important role in re-sensitization of TRAIL.

Discussion

Resistance to TRAIL can occur at the beginning of the treatment (intrinsic) or occur through the selection of a subpopulation of resistant cells during the course of treatment (acquired). Here we tested strategies for overcoming acquired TRAIL resistance. We found that the proteasome inhibitors bortezomib and MG132 resensitized TRAIL-resistant DLD1-TRAIL/R cells to TRAIL by amplifying apoptotic signaling. These results were similar to those of previous studies, which showed that proteasome inhibitors overcame TRAIL resistance in various cancer cell lines 9,20. These previous studies also found that up-regulation of DR4 and DR5 were important for reversing TRAIL resistance 9,20. Our study, showed that both bortezomib and MG132 upregulated DR5, consistent with those previous results in other studies. It was interesting that DR5 upregulation was attenuated when proteasome inhibitor-induced JNK activation was blocked. However, we also found that blocking JNK activation and its correlated attenuation of DR5 upregulation did not affect the level of apoptosis inducted by the combination therapy, suggesting that these events may not play a major role in the proteasome inhibitor-mediated resensitization of DLD1-TRAIL/R cells to TRAIL protein.

However, we found that the proteasome inhibitors induced a dramatic accumulation of Bik protein. Over-expression of Bik, a pro-apoptotic protein, is known to initiate the mitochondrial apoptotic pathway by abrogating the effect of Bcl-XL and Bcl-2, leading to cell death 21,24. Considerable evidence exists shown that activation of the mitochondrial pathway amplifies the death signal from the receptor pathway 25. We also found that, together with Bik accumulation, proteasome inhibitors can induce release of cytochrome C. Moreover, knockdown of Bik expression by Bik siRNA attenuated the apoptosis induction by combination treatment of TRAIL and proteasome inhibitor. Therefore, it is possible that proteasome inhibitor-induced Bik accumulation triggered the mitochondrial apoptotic pathway, which subsequently enhanced TRAIL-induced death signaling, resulting in the reversal of TRAIL resistance in DLD1-TRAIL/R cells. Thus, Bik accumulation might be critical for proteasome inhibitor-mediated reversal of TRAIL resistance.

It has also been reported that proteasome inhibitors might resensitize TRAIL-resistant cells by inhibiting NFκB, although, NFκB was not the final sensor for apoptosis 26. NFκB is a transcriptional factor that regulates more than 200 genes, including Bcl-2, Bcl-XL, and FLIP 27. Our work with DLD1-TRAIL/R cells did not reveal any detectable effects of proteasome inhibitors on Bcl-2, Bcl-XL, and FLIP. It is reported that proteasome inhibitors can inhibit NFκB activity by preventing degradation of IκB. However, our recent study showed that treatment with bortezomib did not result in any detectable change in IκBα levels or in NFκB activity in DLD1 cells 12, suggesting that bortezomib-mediated TRAIL sensitization is independent of NFκB.

In Summary, our data showed that the proteasome inhibitors bortezomib and MG132 can overcome TRAIL resistance, an effect that might be mediated by proteasome inhibitor-induced accumulation of Bik. Thus, using combined treatment with proteasome inhibitors and TRAIL protein might be a useful strategy to simultaneously trigger both death receptor- and mitochondrion- mediated apoptosis pathways and to enhance the anti-tumor activity of these agents.

Acknowledgments

This work was supported in part by National Cancer Institute grants CA 092487-01A1 and CA 098582-01A1 (to B.F.), and CA16672 and by Lockton Grant Matching Fund. This article represents partial fulfillment of the requirements for a Ph.D. degree for J.J.D. We thank Ann Sutton for editorial review and Alma Vega for assistance in preparing the manuscript.

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