Abstract
Constitutive activation of the signal transducer and activator of transcription 3 (Stat3) and mutation of the p53 are both commonly detected in human prostate cancer cells. We sought to investigate whether there is functional regulation of Stat3 by wild-type (wt) p53. Our results demonstrate that expression of wt p53 but not mutant p53 significantly reduced tyrosine phosphorylation of Stat3 and inhibited Stat3 DNA binding activity in both DU145 and Tsu prostate cancer cell lines that express constitutively active Stat3. Expression of the p53 downstream target, p21WAF-1, did not have any inhibitory effect on Stat3 phosphorylation. Wt p53 but not p21WAF-1 induced dramatic apoptosis in these prostate cancer cells. Expression of wt p53 did not cause a reduction of phosphorylation-independent Stat3 protein and reduction of phosphorylation of three unrelated protein kinases, ERK1, ERK2 (ERK1/2), and AKT. Interestingly, p53-dependent apoptosis occurred in the presence of high levels of phosphorylated AKT and ERK1/2 in both DU145 and Tsu prostate cancer cells. Further, we evaluated a series of established human prostate, breast, and ovarian cancer cell lines and found that all cancer cell lines expressing constitutively active Stat3, only harbor mutated or deleted p53. One implication of these results is that the anti-proliferative activities of p53 may not be compatible with the constitutive Stat3 signal in cancer cells.
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References
Bartek J, Iggo R, Gannon J, Lane DP . 1990 Oncogene 5: 893–899
Bowman T, Garcia R, Turkson J, Jove R . 2000 Oncogene 19: 2474–2788
Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell Jr JE . 1998 Mol. Cell. Biol. 18: 2553–2558
Bromberg JF, Wrzeszcznska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell Jr JE . 1999 Cell 98: 295–303
Brown R, Clugston C, Burns P, Edlin A, Vasey P, Vojtesek B, Kaye SB . 1993 Int. J. Cancer 55: 678–684
Burke MW, Jin X, Lin H, Huang M, Liu R, Reynolds YRK, Lin J . 2001 Oncogene 20: 7925–7934
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
Coqueret O, Gascan H . 2000 J. Biol. Chem. 275: 18794–18800
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME . 1997 Cell 91: 231–241
Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M, Finlay C, Levine AJ . 1993 Nat. Genet. 4: 42–46
Elstner E, Linker-Israeli M, Said J, Umiel T, de Vos S, Shintaku IP, Heber D, Binderup L, Uskokovic M, Koeffler HP . 1995 Cancer Res. 55: 2822–2830
Fritsche M, Mundt M, Merkle C, Jahne R, Groner B . 1998 Mol. Cell. Endocrinol. 143: 143–154
Funamoto M, Fujio Y, Kunisada K, Negoro S, Tone E, Osugi T, Hirota H, Izumi M, Yoshizaki K, Walsh K, Kishimoto T, Yamauchi-Takihara K . 2000 J. Biol. Chem. 275: 10561–10566
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
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
Hall MC, Li Y, Pong RC, Ely B, Sagalowsky AI, Hsieh JT . 2000 J. Urol. 163: 1033–1038
Huang M, Page C, Reynolds KR, Lin J . 2000 Gynecologic Oncology 79: 67–73
Isaacs WB, Carter BS, Ewing CM . 1991 Cancer Res. 51: 4716–4720
Jacobberger JW, Sramkoski RM, Zhang D, Zumstein LA, Doerksen LD, Merritt JA, Wright SA, Shults KE . 1999 Cytometry 38: 201–213
Jove R, Niu G, Huang M, Turkson J, Wang T, Zhang S, Sinibaldi D, Coppola D, Heller R, Ellis L, Karras J, Bromberg J, Pardoll D, Yu H . 2001). 92nd AACR Annual Meeting
Katayose D, Gudas J, Nguyen H, Srivastava S, Cowan KH, Seth P . 1995 Clin. Cancer Res. 1: 889–897
Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB . 1992 Sci USA 89: 7491–7495
Lin J, Jin X, Page C, Sondak VK, Jiang G, Reynolds KR . 2000 Cancer Res. 60: 5895–5901
Lin J, Jin X, Rotham K, Lin H, Burke WM . 2002 Cancer Res. 62: 376–380
Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T . 1993 Nature (London) 362: 847–849
Meyers FJ, Gumerlock PH, Chi SG, Borchers H, Deitch AD, deVere White RW . 1998 Cancer 83: 2534–2539
Murphy M, Hinman A, Levine AJ . 1996 Genes Dev. 10: 2971–2980
Navone NM, Troncoso P, Pisters LL, Goodrow TL, Palmer TL, Nichols WW, Eschenbach AC, Conti CJ . 1993 J. Natl. Cancer Inst. 85: 1657–1669
Ni Z, Lou W, Leman ES, Gao AC . 2000 Cancer Res. 60: 1225–1228
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
Palmero I, Pantoja C, Serrano M . 1998 Nature 395: 125–126
Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . 1997 Nature 389: 300–305
Rayanade RJ, Ndubuisi MI, Etlinger JD, Sehgal PB . 1998 J. Immunol. 161: 325–334
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
Tagliaferri P, Tortora G, Guarrasi R, Damiano V, Ruggiero A, Morelli D, Caraglia M, Bianco R, di Isernia G, Pepe S, Arteaga CL, Langton-Webster BC, Bianco AR, Ciardiello F . 1996 Clin. Cancer Res. 2: 207–214
Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R . 1998 Mol. Cell. Biol. 18: 2545–2552
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME . 1995 Science 270: 1326–1331
Yaginuma Y, Westphal H . 1992 Cancer Res. 52: 4196–4199
Zhong Z, Wen Z, Darnell Jr JE . 1994 Science 264: 95–98
Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF . 1998 Genes Dev. 12: 2424–3243
Acknowledgements
We thank Dr Bert Vogelstein at the Johns Hopkins Oncology Center for generously providing the adenovirus p53-175. This work was generously supported in part by the Career Development Award from the University of Michigan Cancer Center Prostate Spore.
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Lin, J., Tang, H., Jin, X. et al. p53 regulates Stat3 phosphorylation and DNA binding activity in human prostate cancer cells expressing constitutively active Stat3. Oncogene 21, 3082–3088 (2002). https://doi.org/10.1038/sj.onc.1205426
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DOI: https://doi.org/10.1038/sj.onc.1205426
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