Cancer Research Meeting Calendar Sign up for Cancer Research eTOC's
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alas, S.
Right arrow Articles by Bonavida, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alas, S.
Right arrow Articles by Bonavida, B.
[Cancer Research 61, 5137-5144, July 1, 2001]
© 2001 American Association for Cancer Research

Immunology

Rituximab Inactivates Signal Transducer and Activation of Transcription 3 (STAT3) Activity in B-Non-Hodgkin’s Lymphoma through Inhibition of the Interleukin 10 Autocrine/Paracrine Loop and Results in Down-Regulation of Bcl-2 and Sensitization to Cytotoxic Drugs1

Steve Alas and Benjamin Bonavida2

Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California Los Angeles School of Medicine, University of California, Los Angeles, California 90095

Development of the chimeric mouse antihuman CD20 antibody, Rituximab, presented a notable advance in the treatment of patients with non-Hodgkin’s lymphoma (NHL). Its use allowed the specific targeting of tumor B cells without the systemic toxicity of traditional therapies. The mechanisms by which Rituximab induces its antitumor activity are not fully understood. We have shown previously that Rituximab down-regulates Bcl-2 expression in some B-NHL cell lymphoma lines through an interleukin 10 (IL-10)-dependent autocrine loop, an effect that renders the resistant cells susceptible to chemotherapeutic drugs. The objective of this study was to delineate the signaling pathway by which Bcl-2 is controlled by Rituximab and IL-10. We hypothesized that the down-regulation of IL-10 by Rituximab decreases activation of the signal transducer and activator of transcription 3 (STAT3) protein, which in turn, is responsible for decreased levels of Bcl-2. We demonstrate by phosphoprotein immunoblotting and gel shift analyses that endogenous IL-10 induces activation of STAT3 in the 2F7 cell line. Furthermore, we show that Rituximab and anti-IL-10 antibody treatment decreases the ability of STAT3 to bind to its DNA binding site. The decrease in STAT3 activation by these treatments correlates with a decrease in Bcl-2 expression. Additionally, piceatannol, an inhibitor of STAT3 activation, down-regulates the expression of Bcl-2. Altogether, these results demonstrate that Bcl-2 expression is under the regulation of the STAT3 signaling pathway, which is regulated by endogenously secreted IL-10. Hence, Rituximab-induced down-regulation of IL-10 expression is responsible for the down-regulation of Bcl-2 and sensitization of NHL cells by therapeutic drugs. Furthermore, these findings support the notion that circulating IL-10 in vivo may control the resistance of NHL to drug-mediated cytotoxicity.




This article has been cited by other articles:


Home page
 JCOHome page
M. Benekli, H. Baumann, and M. Wetzler
Targeting Signal Transducer and Activator of Transcription Signaling Pathway in Leukemias
J. Clin. Oncol., September 10, 2009; 27(26): 4422 - 4432.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
H.-P. Gerber, M. Kung-Sutherland, I. Stone, C. Morris-Tilden, J. Miyamoto, R. McCormick, S. C. Alley, N. Okeley, B. Hayes, F. J. Hernandez-Ilizaliturri, et al.
Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas
Blood, April 30, 2009; 113(18): 4352 - 4361.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. H. Park, S. K. Sohn, J. G. Kim, M.-H. Lee, H. S. Song, M. K. Kim, J. S. Jung, J.-J. Lee, H. J. Kim, and D. H. Kim
Interaction between BCL2 and Interleukin-10 Gene Polymorphisms Alter Outcomes of Diffuse Large B-Cell Lymphoma following Rituximab Plus CHOP Chemotherapy
Clin. Cancer Res., March 15, 2009; 15(6): 2107 - 2115.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
K. Fu, D. D. Weisenburger, W. W.L. Choi, K. D. Perry, L. M. Smith, X. Shi, C. P. Hans, T. C. Greiner, P. J. Bierman, R. G. Bociek, et al.
Addition of Rituximab to Standard Chemotherapy Improves the Survival of Both the Germinal Center B-Cell-Like and Non-Germinal Center B-Cell-Like Subtypes of Diffuse Large B-Cell Lymphoma
J. Clin. Oncol., October 1, 2008; 26(28): 4587 - 4594.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
B. H. Kim, C.-H. Yin, Q. Guo, E. A. Bach, H. Lee, C. Sandoval, S. Jayabose, A. Ulaczyk-Lesanko, D. G. Hall, and G.-H. Baeg
A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells
Mol. Cancer Ther., September 1, 2008; 7(9): 2672 - 2680.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
B. D. Cheson and J. P. Leonard
Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma
N. Engl. J. Med., August 7, 2008; 359(6): 613 - 626.
[Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. H. Olejniczak, F. J. Hernandez-Ilizaliturri, J. L. Clements, and M. S. Czuczman
Acquired Resistance to Rituximab Is Associated with Chemotherapy Resistance Resulting from Decreased Bax and Bak Expression
Clin. Cancer Res., March 1, 2008; 14(5): 1550 - 1560.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. Zhang, L. Gao, Y. Li, G. Lin, Y. Shao, K. Ji, H. Yu, J. Hu, D. V. Kalvakolanu, D. J. Kopecko, et al.
Effects of Plasmid-Based Stat3-Specific Short Hairpin RNA and GRIM-19 on PC-3M Tumor Cell Growth
Clin. Cancer Res., January 15, 2008; 14(2): 559 - 568.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
D. Germain and D. A. Frank
Targeting the Cytoplasmic and Nuclear Functions of Signal Transducers and Activators of Transcription 3 for Cancer Therapy
Clin. Cancer Res., October 1, 2007; 13(19): 5665 - 5669.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Zhang, L. Gao, L. Zhao, B. Guo, K. Ji, Y. Tian, J. Wang, H. Yu, J. Hu, D. V. Kalvakolanu, et al.
Intratumoral Delivery and Suppression of Prostate Tumor Growth by Attenuated Salmonella enterica serovar typhimurium Carrying Plasmid-Based Small Interfering RNAs
Cancer Res., June 15, 2007; 67(12): 5859 - 5864.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
L. H. Sehn, B. Berry, M. Chhanabhai, C. Fitzgerald, K. Gill, P. Hoskins, R. Klasa, K. J. Savage, T. Shenkier, J. Sutherland, et al.
The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP
Blood, March 1, 2007; 109(5): 1857 - 1861.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. J. Stel, B. ten Cate, S. Jacobs, J. W. Kok, D. C. J. Spierings, M. Dondorff, W. Helfrich, H. C. Kluin-Nelemans, L. F. M. H. de Leij, S. Withoff, et al.
Fas Receptor Clustering and Involvement of the Death Receptor Pathway in Rituximab-Mediated Apoptosis with Concomitant Sensitization of Lymphoma B Cells to Fas-Induced Apoptosis
J. Immunol., February 15, 2007; 178(4): 2287 - 2295.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Y. Matsuzaki, Y. Xu, M. Ikegami, V. Besnard, K.-S. Park, W. M. Hull, S. E. Wert, and J. A. Whitsett
Stat3 Is Required for Cytoprotection of the Respiratory Epithelium during Adenoviral Infection
J. Immunol., July 1, 2006; 177(1): 527 - 537.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
N. Mounier, M. Spina, J. Gabarre, M. Raphael, G. Rizzardini, J.-B. Golfier, E. Vaccher, A. Carbone, B. Coiffier, G. Chichino, et al.
AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy
Blood, May 15, 2006; 107(10): 3832 - 3840.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
N. Diaz, S. Minton, C. Cox, T. Bowman, T. Gritsko, R. Garcia, I. Eweis, M. Wloch, S. Livingston, E. Seijo, et al.
Activation of Stat3 in Primary Tumors from High-Risk Breast Cancer Patients Is Associated with Elevated Levels of Activated Src and Survivin Expression
Clin. Cancer Res., January 1, 2006; 12(1): 20 - 28.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
R. D. Blumenthal, H. J. Hansen, and D. M. Goldenberg
Inhibition of Adhesion, Invasion, and Metastasis by Antibodies Targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)
Cancer Res., October 1, 2005; 65(19): 8809 - 8817.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. Gao, L. Zhang, J. Hu, F. Li, Y. Shao, D. Zhao, D. V. Kalvakolanu, D. J. Kopecko, X. Zhao, and D.-Q. Xu
Down-Regulation of Signal Transducer and Activator of Transcription 3 Expression Using Vector-Based Small Interfering RNAs Suppresses Growth of Human Prostate Tumor In vivo
Clin. Cancer Res., September 1, 2005; 11(17): 6333 - 6341.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. R. Jazirehi, S. Huerta-Yepez, G. Cheng, and B. Bonavida
Rituximab (Chimeric Anti-CD20 Monoclonal Antibody) Inhibits the Constitutive Nuclear Factor-{kappa}B Signaling Pathway in Non-Hodgkin's Lymphoma B-Cell Lines: Role in Sensitization to Chemotherapeutic Drug-induced Apoptosis
Cancer Res., January 1, 2005; 65(1): 264 - 276.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. Z. Lin, M. A. Teitell, and G. J. Schiller
The Evolution of Antibodies into Versatile Tumor-Targeting Agents
Clin. Cancer Res., January 1, 2005; 11(1): 129 - 138.
[Abstract] [Full Text] [PDF]

Home page
 ASH Education BookHome page
J. W. Friedberg
Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy
Hematology, January 1, 2005; 2005(1): 329 - 334.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
M. R. Smith, F. Jin, and I. Joshi
Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts
Mol. Cancer Ther., December 1, 2004; 3(12): 1693 - 1699.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
G. Cartron, H. Watier, J. Golay, and P. Solal-Celigny
From the bench to the bedside: ways to improve rituximab efficacy
Blood, November 1, 2004; 104(9): 2635 - 2642.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. R. Jazirehi, M. I. Vega, D. Chatterjee, L. Goodglick, and B. Bonavida
Inhibition of the Raf-MEK1/2-ERK1/2 Signaling Pathway, Bcl-xL Down-Regulation, and Chemosensitization of Non-Hodgkin's Lymphoma B Cells by Rituximab
Cancer Res., October 1, 2004; 64(19): 7117 - 7126.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
B. Sredni, M. Weil, G. Khomenok, I. Lebenthal, S. Teitz, Y. Mardor, Z. Ram, A. Orenstein, A. Kershenovich, S. Michowiz, et al.
Ammonium Trichloro(dioxoethylene-o,o')tellurate (AS101) Sensitizes Tumors to Chemotherapy by Inhibiting the Tumor Interleukin 10 Autocrine Loop
Cancer Res., March 1, 2004; 64(5): 1843 - 1852.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
A. R. Jazirehi, X.-H. Gan, S. De Vos, C. Emmanouilides, and B. Bonavida
Rituximab (anti-CD20) selectively modifies Bcl-xL and apoptosis protease activating factor-1 (Apaf-1) expression and sensitizes human non-Hodgkin's lymphoma B cell lines to paclitaxel-induced apoptosis
Mol. Cancer Ther., November 1, 2003; 2(11): 1183 - 1193.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. D. Khoury, L. J. Medeiros, G. Z. Rassidakis, M. A. Yared, P. Tsioli, V. Leventaki, A. Schmitt-Graeff, M. Herling, H. M. Amin, and R. Lai
Differential Expression and Clinical Significance of Tyrosine-phosphorylated STAT3 in ALK+ and ALK- Anaplastic Large Cell Lymphoma
Clin. Cancer Res., September 1, 2003; 9(10): 3692 - 3699.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
N. Mounier, J. Briere, C. Gisselbrecht, J.-F. Emile, P. Lederlin, C. Sebban, F. Berger, A. Bosly, P. Morel, H. Tilly, et al.
Rituximab plus CHOP (R-CHOP) overcomes bcl-2--associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL)
Blood, June 1, 2003; 101(11): 4279 - 4284.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
B. Mavromatis and B. D. Cheson
Monoclonal Antibody Therapy of Chronic Lymphocytic Leukemia
J. Clin. Oncol., May 1, 2003; 21(9): 1874 - 1881.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Loomis, R. Carbone, M. Reiss, and J. Lacy
Bcl-2 Antisense (G3139, Genasense) Enhances the in Vitro and in Vivo Response of Epstein-Barr Virus-associated Lymphoproliferative Disease to Rituximab
Clin. Cancer Res., May 1, 2003; 9(5): 1931 - 1939.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Benekli, M. R. Baer, H. Baumann, and M. Wetzler
Signal transducer and activator of transcription proteins in leukemias
Blood, April 15, 2003; 101(8): 2940 - 2954.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
Y. Aoki, G. M. Feldman, and G. Tosato
Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma
Blood, February 15, 2003; 101(4): 1535 - 1542.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Alas and B. Bonavida
Inhibition of Constitutive STAT3 Activity Sensitizes Resistant Non-Hodgkin's Lymphoma and Multiple Myeloma to Chemotherapeutic Drug-mediated Apoptosis
Clin. Cancer Res., January 1, 2003; 9(1): 316 - 326.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
H. Schulz, S. K. Klein, U. Rehwald, M. Reiser, A. Hinke, W.-U. Knauf, W.-E. Aulitzky, M. Hensel, M. Herold, D. Huhn, et al.
Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia
Blood, October 16, 2002; 100(9): 3115 - 3120.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. V. Karamouzis, V. G. Gorgoulis, and A. G. Papavassiliou
Transcription Factors and Neoplasia: Vistas in Novel Drug Design
Clin. Cancer Res., May 1, 2002; 8(5): 949 - 961.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Alas, C.-P. Ng, and B. Bonavida
Rituximab Modifies the Cisplatin-mitochondrial Signaling Pathway, Resulting in Apoptosis in Cisplatin-resistant Non-Hodgkin's Lymphoma
Clin. Cancer Res., March 1, 2002; 8(3): 836 - 845.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
B. D. Cheson
CHOP plus Rituximab -- Balancing Facts and Opinion
N. Engl. J. Med., January 24, 2002; 346(4): 280 - 282.
[Full Text] [PDF]

Home page
 JCOHome page
B. D. Cheson
Some Like It Hot!
J. Clin. Oncol., October 1, 2001; 19(19): 3908 - 3911.
[Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2001 by the American Association for Cancer Research.