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[Cancer Research 63, 18-21, January 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Nuclear Factor-{kappa}B p65 Mediates Tumor Necrosis Factor {alpha}-induced Nuclear Translocation of Telomerase Reverse Transcriptase Protein1

Masaharu Akiyama, Teru Hideshima, Toshiaki Hayashi, Yu-Tzu Tai, Constantine S. Mitsiades, Nicholas Mitsiades, Dharminder Chauhan, Paul Richardson, Nikhil C. Munshi and Kenneth C. Anderson2

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 [M. A., T. Hi., T. Ha., Y-T. T., C. S. M., N. M., D. C., P. R., N. C. M., K. C. A.], and Veterans Administration Boston Healthcare System, West Roxbury, Massachusetts 02132 [N. C. M.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Sustained proliferation of cancer cells requires telomerase to maintain telomeres that regulate chromosomal stability and cellular mitosis. Expression of human telomerase reverse transcriptase (hTERT) catalytic subunit, which modulates telomerase activity, is regulated at both the transcriptional level and via phosphorylation by Akt kinase. Moreover, nuclear localization of hTERT is required to promote elongation of telomere sequences. In this study, we show for the first time that hTERT protein interacts directly with nuclear factor (NF)-{kappa}B p65 in MM.1S cells. Importantly, tumor necrosis factor {alpha} (TNF{alpha}) modulates telomerase activity by inducing translocation from the cytoplasm to the nucleus of hTERT protein bound to NF-{kappa}B p65. Conversely, a specific I{kappa}B kinase (IKK) inhibitor PS-1145, and a specific NF-{kappa}B nuclear translocation inhibitor SN-50, both block TNF{alpha}-induced hTERT nuclear translocation. These studies suggest that NF-{kappa}B p65 plays a pivotal role in regulating telomerase by modulating its nuclear translocation.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Telomerase is a ribonucleoprotein DNA polymerase that elongates the telomeres of chromosomes to compensate for losses that occur with each round of DNA replication (1) . Continued proliferation in tumor cells requires this enzyme both to maintain chromosomal stability and to prolong telomere length-regulated cell replication. Conversely, inhibition of telomerase by antisense oligonucleotides (2) and dominant-negative hTERT3 (3) leads to telomere shortening, growth arrest, and cell death in several human tumor cells. The enzymatic activity of telomerase is regulated by hTERT at the transcriptional level. The hTERT promoter contains binding motifs for transcriptional factors including Myc/Mad (E box), Sp1, estrogen, and NF-{kappa}B (4) . Moreover, phosphorylation (5, 6, 7) and the nuclear translocation (6) of hTERT are additional mechanisms regulating telomerase activity. Specifically, up-regulation of telomerase activity in human T lymphocytes is associated with the phosphorylation of hTERT protein and its nuclear translocation (6) . Recently, it has been reported that hTERT protein located in the nucleolus is modulated to nucleoplasm by oncoproteins, as well as by cell cycle and by DNA damage (8, 9, 10) . To date, however, the mechanism regulating cytoplasmic to nuclear translocation of hTERT protein is undefined.

Our previous studies have shown that TNF{alpha} activates NF-{kappa}B (11) , and that telomerase is a downstream target of NF-{kappa}B (7) . Given the requirement for nuclear translocation of activated NF-{kappa}B to modulate gene transcription (12) and its known role in nuclear translocation of tumor suppressor proteins p53 (13) and menin (14) , we in this study determined whether NF-{kappa}B p65 mediated nuclear translocation of hTERT in human MM cells. We demonstrate that hTERT protein interacts directly with NF-{kappa}B p65 in MM.1S cells, and that TNF{alpha} modulates telomerase activity by inducing nuclear translocation of hTERT protein bound to NF-{kappa}B p65. Conversely, a specific IKK inhibitor PS-1145 (15) and a specific NF-{kappa}B nuclear translocation inhibitor SN-50 (16) , both block TNF{alpha}-induced hTERT nuclear translocation. These studies suggest that NF-{kappa}B p65 plays a pivotal role in regulating telomerase activity by modulating its nuclear translocation.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Reagents.
Recombinant human TNF{alpha} (R&D Systems, Minneapolis, MN) was reconstituted with sterile PBS and stored at -20°. Activated recombinant Akt was purchased from Upstate Biotechnology (Lake Placid, NY). IKK inhibitor PS-1145 was obtained from Millennium Pharmaceuticals (Cambridge, MA), and NF-{kappa}B nuclear translocation inhibitor SN-50 was obtained from BIOMOL (Plymouth Meeting, PA).

Cell Line and Cell Culture.
Human MM cell line MM.1S was kindly provided by Dr. Steven Rosen (Northwestern University, Chicago, IL). MM.1S cells were cultured in RPMI 1640 (Mediatech, Herndon, VA) with 10% fetal bovine serum (Harlan, Indianapolis, IN) containing 2 mM L-glutamine, 100 units/ml penicillin, and 100 µg/ml streptomycin (Life Technologies, Inc., Grand Island, NY). Before experimental treatments, MM.1S cells were grown in serum-free media for 24 h.

Telomerase Assay.
The telomerase assay was performed using a TRAPEZE Telomerase Detection kit (Oncor, Gaithersburg, MD). Extracts of whole cells, as well as cytoplasmic and nuclear fractions, were prepared using Nuclear Extract kit (Active Motif, Carlsbad, CA). After incubation with the extracts (50 ng) for 20 min at 30°, PCR amplification was performed with 30 cycles at 94° for 30 s, at 58° for 30 s, and at 72° for 60 s. The PCR products were analyzed by electrophoresis on 12% polyacrylamide nondenaturing gels and stained with SYBR Green I (Molecular Probes, Eugene, OR). Telomerase activity was assessed by determining the ratio of the entire telomerase ladder to that of the internal control, using NIH image analysis software.

Immunoblotting.
Cells were harvested, washed with ice-cold PBS, and lysed with buffer containing 50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1% NP40, 2 mM sodium orthovanadate, and protease inhibitor cocktail (Roche Diagnostics Corp., Indianapolis, IN). An equal amount (100 µg) of the samples was separated on SDS-polyacrylamide gel and then transferred onto nitrocellulose filters (Bio-Rad, Hercules, CA). The membranes were immunoblotted with Abs against hTERT (Calbiochem, La Jolla, CA), NF-{kappa}B p65 (Santa Cruz Biotechnology, Santa Cruz, CA), nucleolin (Santa Cruz Biotechnology), and {alpha}-tubulin (Sigma Chemical, St. Louis, MO). The immunoblots were detected by ECL chemiluminescence (Pharmacia, Uppsala, Sweden).

Immunoprecipitation.
Cells lysates were incubated with anti-hTERT Ab (Calbiochem) or anti-NF-{kappa}B p65 Ab (Santa Cruz Biotechnology) overnight, and then immunoprecipitated for 4 h with protein A-Sepharose (CL-4B; Pharmacia). Immune complexes were washed, electrophoresed, and analyzed by immunoblotting with Abs against hTERT or NF-{kappa}B p65.

We also analyzed the binding of NF-{kappa}B p65 to phosphorylated versus unphosphorylated hTERT proteins. Immunoprecipitates of hTERT in cell lysates were incubated with or without activated recombinant Akt (Upstate Biotechnology) in protein kinase reaction buffer [20 mM HEPES (pH 7.4), 10 mM MgCl2, 1 mM DTT, 1 mM ATP, and 1.3 mM CaCl2] at 30° for 30 min. The reactions were stopped by heating to 95° for 10 min. Phosphorylated and unphosphorylated hTERT proteins were incubated with NF-{kappa}B p65 immunoprecipitates obtained by incubating with NF-{kappa}B TransCruz Oligonucleotide Agarose Conjugates (Santa Cruz Biotechnology) for 4 h, washed, electrophoresed, and analyzed by immunoblotting with Abs against hTERT, phospho-NF-{kappa}B p65 (Cell Signaling, Beverly, MA), and NF-{kappa}B p65.

We next analyzed the binding of hTERT to phosphorylated versus unphosphorylated NF-{kappa}B p65. MM.1S cells were cultured with TNF{alpha} (10 ng/ml) in the presence or absence of PS-1145 (10 µM) for 1 h. MM.1S cell lysates were then immunoprecipitated with Sepharose conjugated to anti-hTERT Ab for 4 h. Immune complexes were washed, electrophoresed, and analyzed by immunoblotting with Abs against hTERT, phospho-NF-{kappa}B p65, and NF-{kappa}B p65.

Cytoplasmic and Nuclear Fractionation.
The preparation of cytoplasmic and nuclear extracts was performed using the Nuclear Extract kit (Active Motif) according to manufacturer’s instructions. Supernatants were harvested as cytoplasmic fractions. Pellets were resuspended in 50 µl of Complete Lysis Buffer and centrifuged at 14,000 x g for 10 min at 4°; supernatants were saved as the nuclear fractions.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Our prior study demonstrated that telomerase activity can be inhibited via down-regulation of hTERT transcription by a specific IKK inhibitor PS-1145, suggesting that NF-{kappa}B regulates telomerase activity in MM cells (7) . The requirement for nuclear localization of hTERT protein to elongate telomere sequences, coupled with the role of nuclear translocation of NF-{kappa}B to either modulate gene transcription (12) , or to transport tumor suppressor proteins (13 , 14) , provided the rationale for our investigation to define whether NF-{kappa}B mediates translocation of hTERT protein from the cytoplasm to the nucleus in MM cells. We found that constitutive association of hTERT protein with NF-{kappa}B p65 protein is transiently up-regulated by TNF{alpha} in MM.1S cells (Fig. 1A and C)Citation , without associated changes in either hTERT (Fig. 1B)Citation or NF-{kappa}B p65 (Fig. 1D)Citation protein expression.



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  		Fig. 1. Direct interaction of NF-{kappa}B p65 with hTERT protein in MM.1S cells. MM.1S cells (1 x 107) were cultured with TNF{alpha} (10 ng/ml) for 0.5 and 1 h. Lysates were incubated with Ab overnight, and then immunoprecipitated (IP) for 4 h with protein A-Sepharose. Immune complexes were washed, electrophoresed, and analyzed by immunoblotting (IB). A, IP anti-hTERT Ab, IB anti-NF-{kappa}B p65 Ab; B, IP anti-hTERT Ab, IB anti-hTERT Ab; C, IP anti-NF-{kappa}B p65 Ab, IB anti-hTERT Ab; D, IP anti-NF-{kappa}B p65 Ab, IB anti-NF-{kappa}B p65 Ab. kDa, Mr in thousands.

 
We next evaluated constitutive and TNF{alpha}-induced NF-{kappa}B p65 and hTERT protein expression in cytoplasmic and nuclear fractions. As shown in Fig. 2ACitation , TNF{alpha} triggers a decrease of NF-{kappa}B p65 protein in cytoplasm (0 h, 78.3%; 0.5 h, 47.8%; 1 h, 41.1%), with a corresponding increase in the nucleus (0 h, 21.7%; 0.5 h, 52.2%; 1 h, 58.9%). A specific IKK inhibitor PS-1145 blocked TNF{alpha}-induced NF-{kappa}B p65 translocation (cytoplasm: 0 h, 78.3%; 0.5 h, 56.1%; 1 h, 69.0%; nucleus: 0 h, 21.7%; 0.5 h, 43.9%; 1 h, 31.0%), as did a specific NF-{kappa}B nuclear translocation inhibitor SN-50 (cytoplasm: 0 h, 78.3%; 0.5 h, 64.9%; 1 h, 67.7%; nucleus: 0 h, 21.7%; 0.5 h, 35.1%; 1 h, 32.3%). Importantly, TNF{alpha} also induced translocation of hTERT protein from the cytoplasm (0 h, 96.2%; 0.5 h, 71.2%; 1 h, 63.3%) to the nucleus (0 h, 3.8%; 0.5 h, 28.8%; 1 h, 36.7%), which was also inhibited by PS-1145 (cytoplasm: 0 h, 97.8%; 0.5 h, 98.3%; 1 h, 98.6%; nucleus: 0 h, 2.2%; 0.5 h, 1.7%; 1 h, 1.4%) and by SN-50 (cytoplasm: 0 h, 97.8%; 0.5 h, 98.2%; 1 h, 97.5%; nucleus: 0 h, 2.2%; 0.5 h, 1.8%; 1 h, 2.5%; Fig. 2BCitation ). These results are representative of three independent experiments and demonstrate that hTERT protein was present in the cytoplasmic fraction of untreated MM.1S cells, and in both cytoplasmic and nuclear fractions after TNF{alpha}-treatment; moreover, PS-1145 and SN-50 inhibited TNF{alpha}-induced nuclear translocation of hTERT protein.



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  		Fig. 2. Nuclear translocation of NF-{kappa}B p65 and hTERT induced by TNF{alpha}. MM.1S cells (1 x 107) were cultured with TNF{alpha} (10 ng/ml) in the presence or absence of PS-1145 (10 µM) or SN-50 (10 µM) for 0.5 h and 1 h. Cytoplasmic (C) and nuclear (N) extracts were separated using the Nuclear Extract kit. A, protein expression of NF-{kappa}B p65 was analyzed by immunoblotting with anti-NF-{kappa}B p65 Ab (left panels). Relative NF-{kappa}B p65 distribution is shown in right panels. B, hTERT protein expression was analyzed by immunoblotting with anti-hTERT Ab. Relative hTERT distribution is shown in right panels. Immunoblotting with anti-nucleolin and anti-{alpha}-tubulin Abs served as positive controls for nuclear and cytoplasmic fractions.

 
We next investigated whether TNF{alpha} induces nuclear translocation of hTERT protein-NF-{kappa}B p65 complexes. TNF{alpha} induced the nuclear translocation of hTERT protein-NF-{kappa}B p65 complexes; PS-1145 inhibited the translocation (Fig. 3, A and B)Citation . Immunoprecipitation followed by immunoblotting with anti-hTERT confirmed that hTERT protein was predominantly in the cytoplasmic fraction of untreated MM.1S cells, whereas it was present in both the cytoplasmic and the nuclear fractions after TNF{alpha}-treatment; moreover, PS-1145 inhibited TNF{alpha}-induced nuclear translocation of hTERT protein (Fig. 3C)Citation . Immunoprecipitation followed by immunoblotting with anti-NF-{kappa}B p65 showed that TNF{alpha} induced nuclear translocation of NF-{kappa}B p65 and that PS-1145 inhibited this process (Fig. 3D)Citation . SN-50 also inhibited TNF{alpha}-induced nuclear translocation of hTERT-NF-{kappa}B p65 complexes (Fig. 3, E and F)Citation .



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  		Fig. 3. Nuclear hTERT protein binding with NF-{kappa}B p65 induced by TNF{alpha}. MM.1S (2 x 107) cells were cultured with TNF{alpha} (10 ng/ml) in the presence or absence of PS-1145 (10 µM) or SN-50 (10 µM) for 1 h. Both cytoplasmic and nuclear extracts were incubated with Ab overnight, and then immunoprecipitated (IP) for 4 h with protein A-Sepharose. Immune complexes were washed, electrophoresed, and analyzed by immunoblotting (IB). A, IP anti-hTERT Ab, IB anti-NF-{kappa}B p65 Ab; B, IP anti-NF-{kappa}B p65 Ab, IB anti-hTERT Ab; C, IP anti-hTERT Ab, IB anti-hTERT Ab; D, IP anti-NF-{kappa}B p65 Ab, IB anti-NF-{kappa}B p65 Ab; E, IP anti-hTERT Ab, IB anti-NF-{kappa}B p65 Ab; F, IP anti-NF-{kappa}B p65 Ab, IB anti-hTERT Ab. G, immunoprecipitates of hTERT in the lysate of MM.1S cells (2 x 107) were incubated with or without the activated recombinant Akt. Phosphorylated and unphosphorylated hTERT proteins were incubated with phosphorylated NF-{kappa}B p65 protein and separated using agarose conjugates containing NF-{kappa}B p65 binding consensus sequences. Immune complexes were washed, electrophoresed, and analyzed by immunoblotting with Abs against hTERT, phospho-NF-{kappa}B p65, and NF-{kappa}B p65. H, MM.1S cells were cultured with TNF{alpha} (10 ng/ml) in the presence or absence of PS-1145 (10 µM) for 1 h. Lysates were incubated with immunoprecipitates of Sepharose conjugated anti-hTERT Ab. Immune complexes were washed, electrophoresed, and analyzed by immunoblotting with Abs against hTERT, phospho-NF-{kappa}B p65, and NF-{kappa}B p65.

 
We next compared the binding of phosphorylated versus unphosphorylated hTERT protein to NF-{kappa}B p65, which was obtained using agarose beads conjugated to NF-{kappa}B binding sequences. hTERT protein, phosphorylated in vitro by recombinant Akt kinase, binds phosphorylated NF-{kappa}B p65 (Fig. 3G)Citation . To compare binding to phosphorylated versus unphosphorylated NF-{kappa}B p65, hTERT protein was separated from whole MM.1S cell lysate using Sepharose conjugates to anti-hTERT Ab. TNF{alpha} induced phosphorylation of NF-{kappa}B p65, which bound hTERT protein; conversely, PS-1145 blocked TNF{alpha}-induced binding of hTERT protein to phosphorylated NF-{kappa}B p65 (Fig. 3H)Citation . These results suggest that phosphorylated NF-{kappa}B p65 mediates the nuclear translocation of phosphorylated hTERT protein.

We next evaluated telomerase activity in TNF{alpha}-treated MM.1S cells. We detected no significant change in telomerase activity in whole cell fractions of treated cells versus control cells: control MM.1S cells (1.00 ± 0.00), PS-1145-treated MM.1S cells (0.92 ± 0.05), SN-50-treated MM.1S cells (0.95 ± 0.07), TNF{alpha}-treated MM.1S cells (1.10 ± 0.05), TNF{alpha} and PS-1145-treated MM.1S cells (1.00 ± 0.10), and TNF{alpha} and SN-50-treated MM.1S cells (1.00 ± 0.10; Fig. 4Citation ). Telomerase activity in untreated control cells was higher in cytoplasmic than in nuclear fractions, and both PS-1145 and SN-50 inhibited telomerase activity in nuclear fraction: 66.3 ± 3.7%, 78.9 ± 1.5%, and 89.8 ± 1.0% in cytoplasm versus 33.6 ± 3.7%, 21.1 ± 1.5%, and 10.2 ± 1.0% in the nucleus of control, PS-1145-treated, and SN-50-treated MM.1S cells, respectively (Fig. 4)Citation . Importantly, TNF{alpha} induced telomerase activity in the nuclear fraction (79.5 ± 2.5%), which was blocked by both PS-1145 (41.1 ± 3.0%) and SN-50 (31.5 ± 4.2%; Fig. 4Citation ). These results suggest that nuclear translocation of hTERT protein and telomerase activity is regulated by phosphorylated NF-{kappa}B p65.



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  		Fig. 4. Effect of NF-{kappa}B on telomerase activity. MM.1S (2 x 107) cells were cultured with or without PS-1145 (10 µM) or SN-50 (10 µM) for 2 h, and then treated with or without TNF{alpha} (10 ng/ml) for 1 h. Whole-cell (W), cytoplasmic (C), and nuclear (N) fractions were prepared using the Nuclear Extract kit and assayed for telomerase activity (top panels). Relative telomerase activity is shown in lower panels. Values represent mean ± SD of triplicate cultures.

 
In MM cells, NF-{kappa}B activation confers resistance to apoptosis and conventional chemotherapy (15 , 17 , 18) . We recently demonstrated that TNF{alpha} in the BM microenvironment induces NF-{kappa}B-dependent alterations in adhesion molecule expression on both MM cells and BM stromal cells, with resulting increased cell adhesion, enhanced tumor cell growth, and cell-adhesion-mediated drug resistance (11) . Excitingly, drugs that abrogate NF-{kappa}B activation in both MM cells and BM microenvironment, including immunomodulatory derivatives of thalidomide (IMiDs) and the proteasome inhibitor PS-341, can overcome drug resistance in preclinical and early clinical studies, and, therefore, have great potential to improve patient outcome (15 , 16 , 19) . Activation of telomerase plays an important role in the evolution from monoclonal gammopathy of undetermined significance to MM (20) , and MM patients with high levels of telomerase activity have poor prognosis (21) . The present study confirms that NF-{kappa}B plays a pivotal role in regulating telomerase via nuclear translocation of hTERT protein, further supporting the potential utility of novel therapeutics targeting NF-{kappa}B in MM.


   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 Supported by NIH Grants RO-1 50947 and PO-1 78378, the Multiple Myeloma Research Foundation (to T. Hi., T. Ha., D. C.), Veterans Affairs Merit Review and Leukemia and Lymphoma Society Scholar in translational research award (to N. C. M.), the Cure Myeloma Fund, the Myeloma Research Fund, and the Doris Duke Distinguished Clinical Research Scientist Award (to K. C. A.). Back

2 To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-2144; Fax: (617) 632-2140; E-mail: kenneth_anderson{at}dfci.harvard.edu Back

3 The abbreviations used are: hTERT, human telomerase reverse transcriptase; MM, multiple myeloma; NF-{kappa}B, nuclear factor {kappa}B; TNF{alpha}, tumor necrosis factor {alpha}; Ab, antibody; BM, bone marrow; IKK, I{kappa}B kinase. Back

Received 9/16/02. Accepted 11/ 8/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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