Abstract
Signal transducers and activators of transcription (STATs) are transcription factors activated in response to cytokines and growth factors. Constitutively active Stat3 has been shown to mediate oncogenic transformation in cultured cells and induce tumor formation in mice. An increasing number of tumor-derived cell lines as well as samples from human cancer have been reported to express constitutively active Stat3 protein. We previously demonstrated that ovarian cancer cell lines express high levels of constitutively active Stat3. In this study, we show that inhibition of the Stat3 signaling pathway using the Janus Kinase-selective inhibitor, AG490, and a dominant negative Stat3 (Stat3β) significantly suppresses the growth of ovarian and breast cancer cell lines harboring constitutively active Stat3. In the ovarian cancer cell lines, AG490 also diminished the phosphorylation of Stat3, Stat3 DNA binding activity, and the expression of Bcl-xL. Further, AG490 induced significant apoptosis in ovarian and breast cancer cell lines expressing high levels of constitutively active Stat3 but had a less profound effect on normal cells lacking constitutively active Stat3. AG490 also enhanced apoptosis induced by cisplatin in ovarian cancer cells. These results suggest that inhibition of Stat3 signaling may provide a potential therapeutic approach for treating ovarian and breast cancers.
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References
Akira S . 1999 Stem Cells 17: 138–146
Akira S . 2000 Oncogene 19: 2607–2611
Bowman T, Garcia R, Turkson J, Jove R . 2000 Oncogene 19: 2474–2488
Briscoe J, Kohlhuber F, Muller M . 1996 Trends Cell. Biol. 6: 336–340
Bromberg J . 2000 Breast Cancer Res. 2: 86–90
Bromberg JF, Wrzeszcznska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell Jr JE . 1999 Cell 98: 295–303
Budde RJ, Ke S, Levin VA . 1994 Cancer Biochem. Biophys. 14: 171–175
Caldenhoven E, Thamar B. van Dijk Solari S, Armstrong J, Raaijmakers J, Lammers J, Koenderman L, de Groot R . 1996 J. Biol. Chem. 271: 13221–13227
Campbell GS, Yu CL, Jove R, Carter-Su C . 1997 J. Biol. Chem. 272: 2591–2594
Catlett-Falcone R, Landowski T, Oshiro M, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna J, Nunez G, Dalton W, Jove R . 1999 Immunity 10: 105–115
Darnell J . 1997 Science 277: 1630–1635
Dole MG, Jasty R, Cooper MJ, Thompson CB, Nunez G, Castle VP . 1995 Cancer Res. 55: 2576–2582
Epling-Burnette PK, Liu JH, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R, Li Y, Wang JM, Yang-Yen HF, Karras J, Jove R, Loughran Jr TP . 2001 J. Clin. Invest. 107: 351–362
Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S, Laudano A, Gazit A, Levitzki A, Kraker A, Jove R . 2001 Oncogene 20: 2499–2513
Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, Ethier SP, Jove R . 1997 Cell Growth Differ. 8: 1267–1275
Hu Y, Benedict MA, Wu D, Inohara N, Nunez G . 1998 Proc. Natl. Acad. Sci. USA 95: 4386–4391
Huang M, Page C, Reynolds KR, Lin J . 2000 Gynecologic Oncology 79: 67–73
Liu JR, Fletcher B, Page C, Hu C, Nunez G, Baker V . 1998 Gynecologic Oncology 70: 398–403
Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM . 1996 Nature 379: 645–648
Minn AJ, Rudin CM, Boise LH, Thompson CB . 1995 Blood 86: 1903–1910
Ni Z, Lou W, Leman ES, Gao A . 2000 Cancer Res. 60: 1225–1228
Nielsen M, Kaestel CG, Eriksen KW, Woetmann A, Stokkedal T, Kaltoft K, Geisler C, Ropke C, Odum N . 1999 Leukaemia 13: 735–738
Niu G, Heller R, Catlett-Falcone R, Coppola Jaroszeski M, Dalton W, Jove R, Yu H . 1999 Cancer Res. 59: 5059–5063
Niu G, Shain KH, Huang M, Ravi R, Bedi A, Dalton WS, Jove R, Yu H . 2001 Cancer Res. 61: 3276–3280
Page C, Huang M, Jin X, Cho K, Lilja J, Reynolds RK, Lin J . 2000 Int. J. Oncol. 17: 23–28
Pan G, O'Rourke K, Dixit VM . 1998 J. Biol. Chem. 273: 5841–5845
Sartor CI, Dziubinski ML, Yu CL, Jove R, Ethier SP . 1997 Cancer Res. 57: 978–987
Shen Y, Devgan G, Darnell Jr JE, Bromberg JF . 2001 Proc. Natl. Acad. Sci. USA. 98: 1543–1548
Song JI, Grandis JR . 2000 Oncogene 19: 2489–2495
Turkson J, Jove R . 2000 Oncogene 19: 6613–6626
Watson CJ, Miller WR . 1995 Br. J. Cancer 71: 840–844
Wiener JR, Nakano K, Kruzelock RP, Bucana CD, Bast Jr RC, Gallick GE . 1999 Clin. Cancer Res. 5: 2164–2170
Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG . 2001 Nat. Genet. 28: 29–35
Zhang Y, Turkson J, Carter-Su C, Smithgall T, Levitzki A, Kraker A, Krolewski JJ, Medveczky P, Jove R . 2000 J. Biol. Chem. 275: 24935–24944
Zhong Z, Wen Z, Darnell Jr JE . 1994 Science 264: 95–98
Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH . 2000 J. Biol. Chem. 275: 5099–5105
Acknowledgements
We thank Stephen Ethier at the University of Michigan for providing the MCF-10A cells and Mats Ljungman at the University of Michigan for providing the normal human skin fibroblasts. We also thank Rupali Patel at the University of Michigan for technical assistance. We acknowledge Richard Jove at the H. Lee Moffitt Cancer Center for providing the Stat3β cDNA. This work was generously supported by a research grant from the Gustavus and Louise Pfeiffer Research Foundation.
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Burke, W., Jin, X., Lin, HJ. et al. Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene 20, 7925–7934 (2001). https://doi.org/10.1038/sj.onc.1204990
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DOI: https://doi.org/10.1038/sj.onc.1204990
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