Novel Small Molecular Inhibitor of STAT3
Note Added in Proof—The images representing GAPDH and STAT3
blots for RH30 cells in Fig. 2E, GAPDH blots for LY5ϩLIF in Fig. 4A,
and the top three subfigures of DMSO-treated cells in Fig. 4D were
mistakenly switched in the original version of Figs. 2 and 4, respec-
tively, that were published on October 13, 2014 as a Paper in Press.
These mistakes have been corrected.
Leventaki, V., Das, P., Rassidakis, G. Z., Cutler, C., Medeiros, L. J., and Lai,
R. (2004) Selective inhibition of STAT3 induces apoptosis and G1 cell
cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 23,
5426–5434
19. Bollrath, J., Phesse, T. J., von Burstin, V. A., Putoczki, T., Bennecke, M.,
Bateman, T., Nebelsiek, T., Lundgren-May, T., Canli, O., Schwitalla, S.,
Matthews, V., Schmid, R. M., Kirchner, T., Arkan, M. C., Ernst, M., and
Greten, F. R. (2009) gp130-mediated Stat3 activation in enterocytes regu-
lates cell survival and cell-cycle progression during colitis-associated tu-
morigenesis. Cancer Cell 15, 91–102
REFERENCES
1. Barton, B. E., Karras, J. G., Murphy, T. F., Barton, A., and Huang, H. F.
(2004) Signal transducer and activator of transcription 3 (STAT3) activa-
tion in prostate cancer: direct STAT3 inhibition induces apoptosis in
prostate cancer lines. Mol. Cancer Ther. 3, 11–20
20. Turkson, J., Bowman, T., Garcia, R., Caldenhoven, E., De Groot, R. P., and
Jove, R. (1998) Stat3 activation by Src induces specific gene regulation and
is required for cell transformation. Mol. Cell. Biol. 18, 2545–2552
21. Bowman, T., Garcia, R., Turkson, J., and Jove, R. (2000) STATs in onco-
genesis. Oncogene 19, 2474–2488
2. Turkson, J., and Jove, R. (2000) STAT proteins: novel molecular targets for
cancer drug discovery. Oncogene 19, 6613–6626
22. Yu, C. L., Meyer, D. J., Campbell, G. S., Larner, A. C., Carter-Su, C.,
Schwartz, J., and Jove, R. (1995) Enhanced DNA-binding activity of a
Stat3-related protein in cells transformed by the Src oncoprotein. Science
269, 81–83
3. Song, H., Wang, R., Wang, S., and Lin, J. (2005) A low-molecular-weight
compound discovered through virtual database screening inhibits Stat3
function in breast cancer cells. Proc. Natl. Acad. Sci. U.S.A. 102,
4700–4705
23. Wang, T., Niu, G., Kortylewski, M., Burdelya, L., Shain, K., Zhang, S.,
Bhattacharya, R., Gabrilovich, D., Heller, R., Coppola, D., Dalton, W., Jove,
R., Pardoll, D., and Yu, H. (2004) Regulation of the innate and adaptive
immune responses by Stat-3 signaling in tumor cells. Nat. Med. 10, 48–54
24. Yu, H., Pardoll, D., and Jove, R. (2009) STATs in cancer inflammation and
immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809
25. Fu, X. Y. (2006) STAT3 in immune responses and inflammatory bowel
diseases. Cell Res. 16, 214–219
4. Darnell, J. E., Jr., Kerr, I. M., and Stark, G. R. (1994) Jak-STAT pathways
and transcriptional activation in response to IFNs and other extracellular
signaling proteins. Science 264, 1415–1421
5. Zhong, Z., Wen, Z., and Darnell, J. E., Jr. (1994) Stat3: a STAT family
member activated by tyrosine phosphorylation in response to epidermal
growth factor and interleukin-6. Science 264, 95–98
6. Bromberg, J. F., Wrzeszczynska, M. H., Devgan, G., Zhao, Y., Pestell, R. G.,
Albanese, C., and Darnell, J. E., Jr. (1999) Stat3 as an oncogene. Cell 98,
295–303
26. Hodge, D. R, Hurt, E. M., and Farrar, W. L. (2005) The role of IL-6 and
STAT3 in inflammation and cancer. Eur. J. Cancer 41, 2502–2512
27. Yu, H., Kortylewski, M., and Pardoll, D. (2007) Crosstalk between cancer
and immune cells: role of STAT3 in the tumour microenvironment. Nat.
Rev. Immunol. 7, 41–51
7. Schlessinger, K., and Levy, D. E. (2005) Malignant transformation but not
normal cell growth depends on signal transducer and activator of tran-
scription 3. Cancer Res. 65, 5828–5834
8. Calò, V., Migliavacca, M., Bazan, V., Macaluso, M., Buscemi, M., Gebbia,
N., and Russo, A. (2003) STAT proteins: from normal control of cellular
events to tumorigenesis. J. Cell Physiol. 197, 157–168
28. Wei, D., Le, X., Zheng, L., Wang, L., Frey, J. A., Gao, A. C., Peng, Z., Huang,
S., Xiong, H. Q., Abbruzzese, J. L., and Xie, K. (2003) Stat3 activation
regulates the expression of vascular endothelial growth factor and human
pancreatic cancer angiogenesis and metastasis. Oncogene 22, 319–329
29. Dechow, T. N., Pedranzini, L., Leitch, A., Leslie, K., Gerald, W. L., Linkov,
I., and Bromberg, J. F. (2004) Requirement of matrix metalloproteinase-9
for the transformation of human mammary epithelial cells by Stat3-C.
Proc. Natl. Acad. Sci. U.S.A. 101, 10602–10607
9. Clark, J., Edwards, S., Feber, A., Flohr, P., John, M., Giddings, I., Crossland,
S., Stratton, M. R., Wooster, R., Campbell, C., and Cooper, C. S. (2003)
Genome-wide screening for complete genetic loss in prostate cancer by
comparative hybridization onto cDNA microarrays. Oncogene 22,
1247–1252
10. Zong, C. S., Zeng, L., Jiang, Y., Sadowski, H. B., and Wang, L. H. (1998)
Stat3 plays an important role in oncogenic Ros- and insulin-like growth
factor I receptor-induced anchorage-independent growth. J. Biol. Chem.
273, 28065–28072
30. Niu, G., Wright, K. L., Huang, M., Song, L., Haura, E., Turkson, J., Zhang,
S., Wang, T., Sinibaldi, D., Coppola, D., Heller, R., Ellis, L. M., Karras, J.,
Bromberg, J., Pardoll, D., Jove, R., and Yu, H. (2002) Constitutive Stat3
activity up-regulates VEGF expression and tumor angiogenesis. Oncogene
21, 2000–2008
11. Kuropatwinski, K. K., De Imus, C., Gearing, D., Baumann, H., and Mosley,
B. (1997) Influence of subunit combinations on signaling by receptors for
oncostatin M, leukemia inhibitory factor, and interleukin-6. J. Biol. Chem.
272, 15135–15144
31. Jones, D. T., Jäger, N., Kool, M., Zichner, T., Hutter, B., Sultan, M., Cho,
Y. J., Pugh, T. J., Hovestadt, V., Stütz, A. M., Rausch, T., Warnatz, H. J.,
Ryzhova, M., Bender, S., Sturm, D., Pleier, S., Cin, H., Pfaff, E., Sieber, L.,
Wittmann, A., Remke, M., Witt, H., Hutter, S., Tzaridis, T., Weischen-
feldt, J., Raeder, B., Avci, M., Amstislavskiy, V., Zapatka, M., Weber, U. D.,
Wang, Q., Lasitschka, B., Bartholomae, C. C., Schmidt, M., von Kalle, C.,
Ast, V., Lawerenz, C., Eils, J., Kabbe, R., Benes, V., van Sluis, P., Koster, J.,
Volckmann, R., Shih, D., Betts, M. J., Russell, R. B., Coco, S., Tonini, G. P.,
Schüller, U., Hans, V., Graf, N., Kim, Y. J., Monoranu, C., Roggendorf, W.,
Unterberg, A., Herold-Mende, C., Milde, T., Kulozik, A. E., von Deimling,
A., Witt, O., Maass, E., Rossler, J., Ebinger, M., Schuhmann, M. U., Fruh-
wald, M. C., Hasselblatt, M., Jabado, N., Rutkowski, S., von Bueren, A. O.,
Williamson, D., Clifford, S. C., McCabe, M. G., Collins, V. P., Wolf, S.,
Wiemann, S., Lehrach, H., Brors, B., Scheurlen, W., Felsberg, J., Reifen-
berger, G., Northcott, P. A., Taylor, M. D., Meyerson, M., Pomeroy, S. L.,
Yaspo, M. L., Korbel, J. O., Korshunov, A., Eils, R., Pfister, S. M., and
Lichter, P. (2012) Dissecting the genomic complexity underlying medullo-
blastoma. Nature 488, 100–105
12. Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A., Ciliberto, G., Furth,
E. E., Poli, V., and Taub, R. (1996) Liver failure and defective hepatocyte
regeneration in interleukin-6-deficient mice. Science 274, 1379–1383
13. Darnell, J. E., Jr. (1997) STATs and gene regulation. Science 277,
1630–1635
14. Bromberg, J., and Darnell, J. E., Jr. (2000) The role of STATs in transcrip-
tional control and their impact on cellular function. Oncogene 19,
2468–2473
15. Turkson, J., Ryan, D., Kim, J. S., Zhang, Y., Chen, Z., Haura, E., Laudano,
A., Sebti, S., Hamilton, A. D., and Jove, R. (2001) Phosphotyrosyl peptides
block Stat3-mediated DNA binding activity, gene regulation, and cell
transformation. J. Biol. Chem. 276, 45443–45455
16. Aoki, Y., Feldman, G. M., and Tosato, G. (2003) Inhibition of STAT3
signaling induces apoptosis and decreases survivin expression in primary
effusion lymphoma. Blood 101, 1535–1542
17. Xu, Q., Briggs, J., Park, S., Niu, G., Kortylewski, M., Zhang, S., Gritsko, T.,
Turkson, J., Kay, H., Semenza, G. L., Cheng, J. Q., Jove, R., and Yu, H.
(2005) Targeting Stat3 blocks both HIF-1 and VEGF expression induced
by multiple oncogenic growth signaling pathways. Oncogene 24,
5552–5560
32. Ling, X., and Arlinghaus, R. B. (2005) Knockdown of STAT3 expression by
RNA interference inhibits the induction of breast tumors in immunocom-
petent mice. Cancer Res. 65, 2532–2536
33. Yang, F., Jove, V., Xin, H., Hedvat, M., Van Meter, T. E., and Yu, H. (2010)
Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor
18. Amin, H. M., McDonnell, T. J., Ma, Y., Lin, Q., Fujio, Y., Kunisada, K.,
3428 JOURNAL OF BIOLOGICAL CHEMISTRY
VOLUME 290•NUMBER 6•FEBRUARY 6, 2015