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J. Biol. Chem., Vol. 281, Issue 47, 35764-35769, November 24, 2006

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Triterpenoid CDDO-Me Blocks the NF-B Pathway by Direct Inhibition of IKK on Cys-179^*

Rehan Ahmad, Deepak Raina, Colin Meyer, Surender Kharbanda, and Donald Kufe¹

From the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 and Reata Pharmaceuticals, Inc., Dallas, Texas 75207

Received for publication, July 27, 2006 , and in revised form, September 14, 2006.

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
The novel oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO) and the C-28 methyl ester (CDDO-Me) induce apoptosis of human tumor cells by disruption of redox balance and are currently in clinical trials. The present studies show that CDDO and CDDO-Me block tumor necrosis factor-induced targeting of NF-B p65 to the nucleus. CDDO-Me also blocked tumor necrosis factor -induced phosphorylation of IB. In concert with these results, we found that CDDO-Me inhibits IB kinase (IKK) activity in cells. In support of a direct mechanism, CDDO-Me inhibited recombinant IKK activity in vitro. The results also demonstrate that (i) CDDO and CDDO-Me form adducts with IKK, but not IKK with mutation of Cys-179 to Ala, and (ii) CDDO-Me inhibits IKK by a mechanism dependent on oxidation of Cys-179. These findings indicate that CDDO and CDDO-Me directly block IKK activity and thereby the NF-B pathway by interacting with Cys-179 in the IKK activation loop.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
The synthetic triterpenoid CDDO² induces differentiation of human myeloid leukemia cells and mouse 3T3-Li fibroblasts (1). CDDO also inhibits cytokine-mediated induction of nitricoxide synthase and functions as a ligand for peroxisome proliferator-activated receptor (1, 2). Other studies have demonstrated that CDDO and its derivatives at the C-28 position induce apoptosis of human myeloid leukemia (3–7), osteosarcoma (8), multiple myeloma (9), lung cancer (10, 11), breast cancer (12, 13), and pancreatic cancer (14) cells. CDDO, the C-28 methyl ester (CDDO-Me), and the C-28 imidazolide ester induce apoptosis by increasing reactive oxygen species and decreasing intracellular glutathione (6, 9, 14, 15). How the CDDO triterpenoids disrupt redox balance is not known. However, the A-ring of these triterpenoids contains an ,-unsaturated carbonyl moiety that can form reversible adducts with reactive thiol groups in dithiothreitol (DTT) (16) or with specific cysteine-rich protein targets (17). These findings have indicated that the CDDO triterpenoids increase reactive oxygen species and induce apoptosis by oxidizing critical cysteines in proteins that regulate redox balance and survival.

NF-B activates the transcription of diverse genes that regulate cell proliferation and survival (18). In the absence of stimulation, the NF-B proteins (RelA/p65, RelB, c-Rel, NF-B1/p50, and NF-B1/p52) localize to the cytoplasm in complexes with members of the IB family of inhibitor proteins (19). Phosphorylation of IB induces ubiquitination and degradation of IB and release of NF-B p65 to the nucleus. In the classical NF-B pathway, the IB kinase (IKK) in a complex with the regulatory IKK subunit is the major kinase responsible for phosphorylation of IB (20). Previous work indicated that CDDO inhibits activation of the NF-B pathway by a mechanism after translocation of NF-B to the nucleus (5). The present results demonstrate that CDDO and CDDO-Me block the NF-B pathway by inhibiting IKK. The results also indicate that CDDO and CDDO-Me directly inhibit IKK by interacting with Cys-179 in the IKK activation loop.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Cell Culture—Human U-937 myeloid leukemia cells were grown in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum, 100 units/ml penicillin, 100 µg/ml streptomycin, and 2 mM L-glutamine. 293 cells were grown in Dulbecco's modified Eagle's medium containing 10% heat-inactivated fetal bovine serum, antibiotics, and L-glutamine. Cells were treated with CDDO or CDDO-Me (provided by Reata Pharmaceuticals), human TNF- (20 ng/ml; BD Biosciences), the proteasome inhibitor MG-132 (25 µM; Calbiochem), or DTT (300 µM; Sigma).

Subcellular Fractionation—Nuclear and cytosolic fractions were prepared as described (21).

Immunoprecipitation and Immunoblot Analysis—Lysates from subconfluent cells were prepared as described (22). Soluble proteins were incubated with anti-IKK (Cell Signaling Technology) or anti-FLAG (Sigma) and precipitated with protein A/G beads. Immune complexes or cell lysates were subjected to immunoblotting with anti-NF-B p65 (Santa Cruz Biotechnology), anti-lamin B (Calbiochem), anti-IB (Santa Cruz Biotechnology), anti--tubulin (Santa Cruz Biotechnology), anti-phospho-IB (Cell Signaling Technology), anti--actin (Sigma), anti-IKK, anti-phospho-IKK (Cell Signaling Technology), anti-Bcl-2, anti-Bcl-xL (Santa Cruz Biotechnology), or anti-FLAG (Sigma). The immune complexes were detected with horseradish peroxidase-conjugated second antibodies and enhanced chemiluminescence (ECL; Amersham Biosciences).

View larger version (43K): [in this window] [in a new window]   FIGURE 1. CDDO-Me inhibits NF-B activation by attenuating IB phosphorylation. A, U-937 cells were pretreated with 0.25, 0.5, or 1.0 µM CDDO-Me for 6 h and then stimulated with TNF- for 15 min. Nuclear lysates were immunoblotted with anti-NF-B p65 and, as controls for equal loading and purity, with antibodies against nuclear lamin B, cytosolic IB, and cytosolic -tubulin. WCL, whole cell lysate. B, cells were treated with 1.0 µM CDDO-Me for 2 h, and then TNF- was added for the indicated times. Whole cell lysates were immunoblotted with antibodies against Bcl-xL, Bcl-2, and -actin. C, cells were treated with 0.25, 0.5, or 1.0 µM CDDO-Me for 6 h and with 25 µM MG-132 for 1 h to inhibit the proteasome. The cells were then stimulated with TNF- for 15 min. Cytosolic lysates were immunoblotted with anti-phospho-IB, anti-IB, and anti--actin.

IKK Kinase Assays—Anti-IKK precipitates or recombinant His-IKK (Upstate Cell Signaling Solutions) were incubated in kinase buffer (50 mM HEPES, pH 7.4, 10 mM MgCl₂, 10 mM MnCl₂, 0.1 mM sodium vanadate, 10 µM ATP, and 1 mM DTT) with GST-IB and [-³²P]ATP (PerkinElmer Life Sciences) for 30 min at 30 °C. DTT was omitted from the reactions where indicated. The reaction products were analyzed by SDS-PAGE and autoradiography.

Generation of IKK(C179A) Mutant—Mutation of IKK Cys-179 to Ala was generated by site-directed mutagenesis (Stratagene) using pGEX-IKK as the template and confirmed by DNA sequencing. IKK and IKK(C179A) were purified after cleavage with thrombin to remove the GST moiety.

Binding of CDDO-Me-biotin and CDDO-biotin to IKK—CDDO and CDDO-Me were biotinylated as described (23). For in vitro binding studies, (i) anti-FLAG precipitates from 293 cells expressing FLAG-IKK or FLAG-IKK(C179A) were incubated with 5 µM CDDO-biotin, and (ii) recombinant IKK or IKK(C179A) was incubated with 1 µM CDDO-Me-biotin or 5 µM CDDO-biotin. For in vivo studies, 293 cells expressing FLAG-IKK or FLAG-IKK(C179A) were cultured with 5 µM CDDO-biotin. Lysates were then precipitated with anti-FLAG. Proteins were separated by SDS-PAGE and transferred to nitrocellulose membranes. After washing, the membranes were incubated with streptavidin horseradish peroxidase (Amersham Biosciences) and developed with enhanced chemiluminescence (ECL; Amersham Biosciences).

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
CDDO-Me Inhibits NF-B p65 Activation by Blocking IB Phosphorylation—To assess the effects of CDDO-Me on regulation of the NF-B pathway, we stimulated human U-937 myeloid leukemia cells with TNF- to induce translocation of NF-B p65 to the nucleus (Fig. 1A). Treatment of the TNF--stimulated cells with CDDO-Me was associated with a concentration-dependent decrease in nuclear translocation of p65 (Fig. 1A). Equal loading and purity of the nuclear lysates was confirmed by immunoblotting with antibodies against nuclear lamin B, cytosolic IB, and cytosolic-tubulin (Fig. 1A). In concert with these results, TNF--induced expression of Bcl-2 and Bcl-xL, which is activated by NF-B (18), was attenuated by CDDO-Me treatment, a response delayed compared with that for nuclear translocation of p65 (Fig. 1B). Similar findings were obtained when the TNF--stimulated cells were treated with the parent compound, CDDO (data not shown), indicating that this effect is not selective for the methyl ester. NF-B p65 is released from cytosolic IB and targeted to the nucleus in response to phosphorylation and ubiquitination of IB (24). To determine whether CDDO-Me affects IB phosphorylation, cytosolic lysates from TNF--stimulated cells were immunoblotted with anti-phospho-IB. The results demonstrate that CDDO-Me inhibits TNF--induced phosphorylation of IB (Fig. 1C). In concert with these results, CDDO and CDDO-Me also inhibited TNF--induced degradation of IB (Fig. 1C). These findings indicate that CDDO and CDDO-Me act upstream to IB in the NF-B pathway.

View larger version (39K): [in this window] [in a new window]   FIGURE 2. CDDO-Me inhibits IKK kinase activity. A and B, cells were pretreated with 0.25 and 0.5 µM CDDO-Me for 6 h and then stimulated with TNF- for 15 min. A, anti-IKK precipitates were incubated in kinase reactions with GST-IB and [-32P]ATP. The reaction products were analyzed by SDS-PAGE and autoradiography. The precipitates were also immunoblotted with anti-IKK. B, lysates were immunoblotted with antiphospho-IKK-Ser-181 and anti-IKK. C, anti-IKK precipitates from control and TNF--treated cells were incubated with 0.25 and 0.5 µM CDDO-Me in kinase buffer (without and with 1 mM DTT) containing GST-IB and [-32P]ATP. The reaction products were analyzed by SDS-PAGE and autoradiography. The precipitates were also immunoblotted with anti-IKK. D, kinase-active His-IKK was incubated with 0.25 and 0.5µM CDDO-Me for 10 min at 30 °C. IKK activity was then assayed in kinase buffer without (left) and with 1 mM DTT (right) containing GST-IB and [-32P]ATP. The reaction products were analyzed by SDS-PAGE and autoradiography. Equal loading of His-IKK and GST-IB was determined by immunoblotting.

View larger version (35K): [in this window] [in a new window]   FIGURE 3. CDDO-Me inhibits IKK by modification of Cys-179. A, 293 cells were transfected with FLAG-IKK or FLAG-IKK(C179A). At 48 h after transfection, the cells were treated with 0.25 and 0.5 µM CDDO-Me for 6 h. Anti-FLAG precipitates were incubated in kinase reactions containing GST-IB and [-32P]ATP. The reaction products were analyzed by SDS-PAGE and autoradiography. The precipitates were also immunoblotted with anti-IKK. B, 293 cells were transfected with FLAG-IKK or FLAG-IKK(C179A). At 48 h after transfection, lysates were immunoprecipitated with anti-FLAG. The precipitates were incubated with 0.25 and 0.5 µM CDDO-Me in kinase buffer (no DTT) containing GST-IB and [-32P]ATP. The reaction products and precipitates were analyzed as described in panel A. C, 293 cells were cotransfected with pNF-B-Luc, SV-40-Renilla-Luc, and FLAG-IKK or FLAG-IKK(C179A). At 24 h after transfection, cells were treated with 0.25 and 0.5 µM CDDO-Me for 6 h and then assayed for luciferase activity. The results are expressed as the fold activation (mean ± S.D. of three separate experiments) relative to that obtained with the FLAG-IKK control (lane 1, assigned a value of 1).

CDDO-Me Inhibition of IKK Is Reversed by Mutation of Cys-179—IKK contains a cysteine at position 179 in its activation loop. To determine whether this cysteine is involved in inhibition by CDDO-Me, we transfected 293 cells to express wild-type FLAG-IKK or FLAG-IKK with a C179A mutation. Analysis of anti-FLAG precipitates for phosphorylation of GST-IB demonstrated similar levels of activity for FLAG-IKK and FLAG-IKK(C179A) (Fig. 3A). CDDO-Me treatment was associated with inhibition of wild-type IKK (Fig. 3A). By contrast, CDDO-Me had no apparent effect on IKK(C179A) activity (Fig. 3A). In concert with these results, CDDO-Me also had little effect on IKK(C179) activity when added directly to in vitro kinase assays (Fig. 3B). Moreover, CDDO-Me-induced inhibition of NF-B-mediated transcription was substantially attenuated in cells expressing IKK(C179A) as compared with that obtained with wild-type IKK (Fig. 3C). These findings indicate that CDDO-Me inhibits IKK by reacting with Cys-179.

View larger version (34K): [in this window] [in a new window]   FIGURE 4. CDDO-Me inhibits IKK by oxidizing Cys-179. A, recombinant IKK or IKK(C179A) was incubated with 1 µM CDDO-Me-biotin for 1 h. The reaction products were analyzed by SDS-PAGE, transfer of proteins to a nitrocellulose membrane, and detection with streptavidin horseradish peroxidase. B, left, recombinant IKK was incubated with 1 µM CDDO-Me-biotin and 0 (–), 1 (+), or 5 (++) µM unlabeled CDDO-Me. The reaction products were analyzed as described in panel A. Right, kinase-active His-IKK was incubated with 1 µM CDDO-Me or 1 µM CDDO-Me-biotin for 10 min at 30 °C. IKK activity was then assayed in kinase buffer (without DTT) containing GST-IB and [-32P]ATP. The reaction products were analyzed by SDS-PAGE and autoradiography. Equal loading of His-IKK and GST-IB was determined by immunoblotting. C, 293 cells expressing IKK or IKK(C179A) were treated with CDDO-Me for 6 h. Lysates were immunoblotted with anti-IKK and anti--actin. The asterisk (*) identifies the position of the higher molecular mass species that reacts with anti-IKK. D and E, U-937 cells were pretreated with 300 µM DTT for 1 h and/or 1 µM CDDO-Me for an additional 6 h before stimulation with TNF- for 15 min. Cytosolic lysates (D) were immunoblotted with anti-phospho-IB, anti-IB, and anti--actin. Nuclear lysates (E) were immunoblotted with the indicated antibodies.

View larger version (45K): [in this window] [in a new window]   FIGURE 5. CDDO also interacts directly with IKK. A, anti-FLAG precipitates from 293 cells expressing FLAG-IKK or FLAG-IKK(C179A) were incubated with 5 µM CDDO-biotin for 1 h. The reaction products were analyzed by SDS-PAGE, transfer of proteins to a nitrocellulose membrane, and detection with streptavidin horseradish peroxidase. B, 293 cells expressing FLAG-IKK or FLAG-IKK(C179A) were cultured with 5 µM CDDO-biotin for 6 h. Anti-FLAG precipitates were analyzed by SDS-PAGE, transfer to a nitrocellulose membrane, and detection with streptavidin horseradish peroxidase. C, recombinant IKK or IKK(C179A) was incubated with 5 µM CDDO-biotin for 1 h. The reaction products were analyzed by SDS-PAGE, transfer of proteins to a nitrocellulose membrane, and detection with streptavidin horseradish peroxidase. D, schema depicting CDDO/CDDO-Me inhibition of IKK and the NF-B pathway.

CDDO-Me Functions as an Electrophile in Inhibiting IKK—CDDO contains an ,-unsaturated carbonyl in the A-ring that forms reversible adducts with thiol nucleophiles (16). Other studies have shown that Cys-179 in the IKK activation loop is sensitive to modification by cyclopentenone prostaglandins that also contain an ,-unsaturated carbonyl moiety (28). The present studies demonstrate that CDDO-Me directly inhibits IKK activity and thereby the NF-B pathway (Fig. 5D). Previous work has indicated that CDDO inhibits the NF-B pathway following nuclear translocation of p65 (5). In addition, since submission of the present work, another study has reported that CDDO-Me inhibits the NF-B pathway and that CDDO-Me is not a direct inhibitor of IKK (29). By contrast, our results clearly demonstrate that CDDO and CDDO-Me interact directly with IKK. CDDO-Me-induced inhibition of IKK in vitro and in cells was reversed by DTT, which forms reversible adducts with CDDO, indicating that, like the cyclopentenone prostaglandins, CDDO-Me inhibits IKK by oxidation of a reactive cysteine moiety. Similar results were obtained with CDDO, indicating that the presence of the methyl ester is not required for direct interaction with the IKK Cys-179 residue. Moreover, the findings that (i) IKK with a C179A mutation is insensitive to the effects of CDDO-Me and (ii) CDDO-Me and CDDO bind directly to IKK, but not IKK(C179A), in vitro and in cells support oxidation of the thiol group on Cys-179 as the inhibitory mechanism. Thus, the anti-inflammatory effects of CDDO and its derivatives (1) may, like the cyclopentenone prostaglandins, be mediated by inhibiting IKK. The CDDO triterpenoids are also potent inducers of apoptosis by a mechanism involving in part the activation of JNK (15). In this context, inhibition of NF-B sensitizes cells to the induction of apoptosis by sustained activation of JNK (30). Direct inhibition of IKK and thereby the NF-B pathway by CDDO or its derivatives could therefore contribute to the apoptotic response of tumor cells to treatment with these agents.

	FOOTNOTES

 
^* This work was supported by NCI, National Institutes of Health Grants CA42802, CA100707, and CA98628. 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 correspondence should be addressed. Tel.: 617-632-3141; Fax: 617-632-2934; E-mail: donald_kufe{at}dfci.harvard.edu.

² The abbreviations used are: CDDO, 2-cyano-3,12-dioxooleana-1,9,-dien-28oic acid; CDDO-Me, CDDO methyl ester; IKK, IB kinase; DTT, dithiothreitol; TNF-, tumor necrosis factor ; GST, glutathione S-transferase; JNK, c-Jun N-terminal kinase.

	ACKNOWLEDGMENTS

 
We thank Dr. Thomas Gilmore, Boston University, for the FLAG-IKK and FLAG-IKK(C179A) vectors and Dr. Michael Karin for GST-IKK. Kamal Chauhan is acknowledged for technical support.

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