This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alas, S. Articles by Bonavida, B. Search for Related Content PubMed PubMed Citation Articles by Alas, S. Articles by Bonavida, B.

Inhibition of Constitutive STAT3 Activity Sensitizes Resistant Non-Hodgkin’s Lymphoma and Multiple Myeloma to Chemotherapeutic Drug-mediated Apoptosis¹

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

Hematopoietic malignancies have been shown to depend on cytokine growth factor autocrine/paracrine loops for growth and differentiation. This results in the constitutive activation of cytokine-mediated transcription factors like signal transducer and activators of transcription (STAT) 3 in non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Recent evidence demonstrates that cytokines also contribute to a drug-resistant phenotype in many tumor cell types. We hypothesized that inhibitors of the STAT3 pathway would sensitize drug-resistant and endogenous cytokine-dependent NHL and MM tumor cells to the cytotoxic effects of chemotherapeutic drugs. We examined an AIDS-related NHL cell line, 2F7, known to be dependent on interleukin (IL)-10 for survival and an MM cell line, U266, known to be dependent on IL-6 for survival. IL-10 and IL-6 signal the cells through the activation of Janus kinase (JAK)1 and JAK2, respectively. Thus, we investigated the effect of two chemical STAT3 pathway inhibitors, namely, piceatannol (JAK1/STAT3 inhibitor) and tyrphostin AG490 (JAK2/STAT3 inhibitor), on the tumor cells for sensitization to therapeutic drugs. We demonstrate by phosphoprotein immunoblotting analysis and electrophoretic mobility shift analysis that piceatannol and AG490 inhibit the constitutive activity of STAT3 in 2F7 and U266, respectively. Furthermore, piceatannol and AG490 sensitize 2F7 and U266 cells, respectively, to apoptosis by a range of therapeutic drugs including cisplatin, fludarabine, Adriamycin, and vinblastine. The specificity of the inhibitors was corroborated in experiments showing that piceatannol had no effect on U266 and, likewise, AG490 has no effect on 2F7. The sensitization observed by these inhibitors correlated with the inhibition of Bcl-2 expression in 2F7 and Bcl-xL expression in U266. Altogether, these results demonstrate that STAT3 pathway inhibitors are a novel class of chemotherapeutic sensitizing agents capable of reversing the drug-resistant phenotype of cytokine-dependent tumor cells.

This article has been cited by other articles:

				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]

				T. Khong, J. Sharkey, and A. Spencer The effect of azacitidine on interleukin-6 signaling and nuclear factor-{kappa}B activation and its in vitro and in vivo activity against multiple myeloma Haematologica, June 1, 2008; 93(6): 860 - 869. [Abstract] [Full Text] [PDF]

				V. R. Fantin, A. Loboda, C. P. Paweletz, R. C. Hendrickson, J. W. Pierce, J. A. Roth, L. Li, F. Gooden, S. Korenchuk, X. S. Hou, et al. Constitutive Activation of Signal Transducers and Activators of Transcription Predicts Vorinostat Resistance in Cutaneous T-Cell Lymphoma Cancer Res., May 15, 2008; 68(10): 3785 - 3794. [Abstract] [Full Text] [PDF]

				D. A Frank Targeting Transcription Factors for Cancer Therapy Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 335 - 341. [Abstract] [Full Text] [PDF]

				Z. Duan, J. Bradner, E. Greenberg, R. Mazitschek, R. Foster, J. Mahoney, and M. V. Seiden 8-Benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic Acid (SD-1008), a Novel Janus Kinase 2 Inhibitor, Increases Chemotherapy Sensitivity in Human Ovarian Cancer Cells Mol. Pharmacol., November 1, 2007; 72(5): 1137 - 1145. [Abstract] [Full Text] [PDF]

				J. Yang, X. Zhang, J. Wang, J. Qian, L. Zhang, M. Wang, L. W. Kwak, and Q. Yi Anti {beta}2-microglobulin monoclonal antibodies induce apoptosis in myeloma cells by recruiting MHC class I to and excluding growth and survival cytokine receptors from lipid rafts Blood, October 15, 2007; 110(8): 3028 - 3035. [Abstract] [Full Text] [PDF]

				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]

				L. Pedranzini, T. Dechow, M. Berishaj, R. Comenzo, P. Zhou, J. Azare, W. Bornmann, and J. Bromberg Pyridone 6, A Pan-Janus-Activated Kinase Inhibitor, Induces Growth Inhibition of Multiple Myeloma Cells Cancer Res., October 1, 2006; 66(19): 9714 - 9721. [Abstract] [Full Text] [PDF]

				T. Rubic and R. L. Lorenz Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10 Cardiovasc Res, February 1, 2006; 69(2): 527 - 535. [Abstract] [Full Text] [PDF]

				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]

				R. Buzzeo, S. Enkemann, R. Nimmanapalli, M. Alsina, M. G. Lichtenheld, W. S. Dalton, and D. M. Beaupre Characterization of a R115777-Resistant Human Multiple Myeloma Cell Line with Cross-Resistance to PS-341 Clin. Cancer Res., August 15, 2005; 11(16): 6057 - 6064. [Abstract] [Full Text] [PDF]

				L. Y. Dimberg, A. I. Dimberg, K. Ivarsson, T. Stromberg, A. Osterborg, K. Nilsson, F. Oberg, and H. J. Wiklund Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells Blood, August 15, 2005; 106(4): 1346 - 1354. [Abstract] [Full Text] [PDF]

				H. Song, R. Wang, S. Wang, and J. Lin A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells PNAS, March 29, 2005; 102(13): 4700 - 4705. [Abstract] [Full Text] [PDF]

				B. E. Barton, J. G. Karras, T. F. Murphy, A. Barton, and H. F-S. Huang Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines Mol. Cancer Ther., January 1, 2004; 3(1): 11 - 20. [Abstract] [Full Text]