STAT3 inhibition induces apoptosis in cancer cells independent of STAT1 or STAT2

Adetola Shodeinde, Kalyani Ginjupalli, H. Dan Lewis, Sheraz Riaz, Beverly E Barton


Signal transducers and activators of transcription (STATs) were originally discovered as mediators of signal transduction. Persistent aberrant activation of STAT3 is part of the malignant phenotype of hormone-refractory prostate cancer and pancreatic cancer; this is thought to be mediated by homodimers of phosphorylated STAT3, which translocate to the nucleus.  One consequence of persistently-activated STAT3 in malignant cells is that they depend upon it for survival.   STAT3 is observed to heterodimerize with STAT1 and STAT2; however the contributions of STAT3:STAT1  and STAT3:STAT2 heterodimers to the survival of malignant cells have not been investigated in detail.

Previously we reported that single-stranded oligonucleotides containing consensus STAT3 binding sequences (13410 and 13411) were more effective for inducing apoptosis in prostate cancer cells than antisense STAT3 oligonucleotides. Control oligonucleotides (scrambled sequences) had no effect. STAT3-inhibiting oligonucleotide 13410, but not scrambled-sequence oligonucleotides, induced apoptosis in pancreatic cancer cells as well.  Here we report that 13410 and derivative olignucleotides induced apoptosis in STAT1-null and STAT2-null fibrosarcoma cell lines U3A and U6A, as well as in the parental fibrosarcoma cell line 2fTGH. The cell lines expressed constitutively-activated STAT3 and depended on its activity for survival.  Forty-eight hr after transfection of 13410 or related oligonucleotides, significant apoptosis was observed in 2fTGH, U3A and U6A cells. Scrambled-sequence oligonucleotides had no effect on survival.  These data indicate that neither STAT1 nor STAT2 play significant roles in the maintenance of these cells, and by extension that STAT3:STAT1 and STAT3:STAT2 heterodimers regulate a different set of genes from STAT3:STAT3 homodimers.




STAT1; STAT2; STAT3; prostate cancer; pancreatic cancer; inhibitors


Barton BE, Karras JG, Murphy TF, Barton AB & Huang HF 2004a STAT3 Activation in Prostate Cancer: Direct STAT3 Inhibition Induces Apoptosis in Prostate Cancer Lines. Mol Cancer Ther 3 11-20.

Barton BE, Murphy TF, Adem P, Watson RA, Irwin RJ & Huang HS 2001 IL-6 signaling by STAT3 participates in the change from hyperplasia to neoplasia in NRP-152 and NRP-154 rat prostatic epithelial cells. BMC Cancer 1 19.

Barton BE, Murphy TF, Shu P, Huang HF, Meyenhofen M & Barton AB 2004b Novel Single-Stranded Oligonucleotides that Inhibit STAT3 Induce Apoptosis In Vitro and In Vivo in Prostate Cancer Cell Lines. Mol Cancer Ther 3 1183-1191.

Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C & Darnell JE 1999 Stat3 as an oncogene. Cell 98 295-303.

Buettner R, Mora LB & Jove R 2002 Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8 945-954.

Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernández-Luna JL, Nuñez G, Dalton WS & Jove R 1999 Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10 105-115.

Clifford JL, Yang X, Walch E, Wang M & Lippman SM 2003 Dominant negative signal transducer and activator of transcription 2 (STAT2) protein: stable expression blocks interferon alpha action in skin squamous cell carcinoma cells. Molecular Cancer Therapeutics 2 453-459.

Darnell Jr JE 2005 Validating Stat3 in cancer therapy. Nat Med 11 595-596.

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 TP Jr 2001 Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 107 351-362.

Ernst M, Najdovska M, Grail D, Lundgren-May T, Buchert M, Tye H, Matthews VB, Armes J, Bhathal PS, Hughes NR, Marcusson EG, Karras JG, Na S, Sedgwick JD, Hertzog PJ & Jenkins BJ 2008 STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest 118 1727-1738.

Gimeno R, Lee CK, Schindler C & Levy DE 2005 Stat1 and Stat2 but not Stat3 arbitrate contradictory growth signals elicited by alpha/beta interferon in T lymphocytes. Mol Cell Biol 25 5456-5465.

Goethe JW, Bittova M, Vogel JU, Kotchekov R, Doerr HW & Cinati Jr. J 2001 Antisense oligonucleotide ISIS 2922 targets IE-expression and prevents HCMV-IE-induced suppression of TSP-1 and TSP-2 expression. Nucleosides Nucleotides Nucleic Acids 20 1425-1428.

Grandis JR, Drenning SD, Chakraborty A, Zhou M-Y, Zang Q, Pitt AS & Tweardy DJ 1998 Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro. J Clin Invest 102 1385-1392.

Gregersen LH, Jacobsen AB, Frankel LB, Wen J, Krogh A & Lund AH 2010 MicroRNA-145 targets YES and STAT1 in colon cancer cells. PLoS One 5 e8836.

Guvakova MA, Yakubov LA, Vlodavesky I, Tonkinson JL & Stein CA 1995 Phosphothiorate oligodeoxynucleotides bind to basic fibroblast growth factor, inhibit its binding to cell surface receptors, and remove it from low affinity binding sites on extracellular matrix. J Biol Chem 270 2620-2627.

Harir N, Pecquet C, Kerenyi M, Sonneck K, Kovacic B, Nyga R, Brevet M, Dhennin I, Gouilleux-Gruart V, Beug H, Valent P, Lassoued K, Moriggl R & Gouilleux F 2007 Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias. Blood 109 1678-1686.

Huang Y, Qiu, J, Dong S, Redell MS, Poli V, Mancini MA & Tweardy DJ 2007 Stat3 isoforms, alpha and beta, demonstrate distinct intracellular dynamics with prolonged nuclear retention of Stat3beta mapping to its unique C-terminal end. J Biol Chem 282 34958-34967.

Ichiba M, Miyazaki Y, Kitamura S, Kiyohara T, Shinomura Y & Matsuzawa Y 2002 Epidermal growth factor inhibits the growth of TE8 esophageal cancer cells through the activation of STAT1. J Gastroenterol 37 497-505.

Ihle JN 1996 STATs and MAPKs: obligate or opportunistic partners in signaling. BioEssays 18 95-98.

Khodarev NN, Beckett M, Lebay E, Darga T, Roizman B & Weichselbaum RR 2004 STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells. Proc Natl Acad Sci USA 101 1714-1719.

Khodarev NN, Minn AJ, Efimova EV, Darga TE, Labay E, Beckett M, Mauceri HJ, Roizman B & Weichselbaum RR 2007 Signal Transducer and Activator of Transcription 1 Regulates Both Cytotoxic and Prosurvival Functions in Tumor Cells. Cancer Res 67 9214-9220.

Kovacic B, Stoiber D, Moriggl R, Weisz E, Ott RG, Kreibich R, Levy DE, Beug H, Freissmuth M & Sexl V 2006 STAT1 acts as a tumor promoter for leukemia development. Cancer Cell 10 77-87.

Lehnhardt M, Klein-Hitpass L, Kuhnen C, Homann HH, Daigeler A, Steinau HU, Roehrs S, Schnoor L, Steinstraesser L & Mueller O 2005 Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways. BMC Cancer 5 74.

Lesinski GB, Valentino D, Hade EM, Jones S, Magro C, Chaudhury AR, Walker MJ & Carson WE 3rd 2005 Expression of STAT1 and STAT2 in malignant melanoma does not correlate with response to interferon-alpha adjuvant therapy. Cancer Immunol Immunother 54 815-825.

Lewis HD, Winter A, Murphy TF, Tripathi S, Pandey VN & Barton BE 2008 STAT3 inhibition in prostate and pancreatic cancer lines by STAT3 binding sequence oligonucleotides: differential activity between 5' and 3' ends. Mol Cancer Ther 7 1543-1550.

Li X, Leung S, Qureshi S, Darnell JE Jr & Stark GR 1996 Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alpha. J Biol Chem 271 5790-5794.

Lui VW, Boehm AL, Koppikar P, Leeman RJ, Johnson D, Ogagan M, Childs E, Freilino M & Grandis JR 2007 Antiproliferative Mechanisms of a Transcription Factor Decoy Targeting Signal Transducer and Activator of Transcription (STAT) 3: The Role of STAT1. Mol Pharmacol 71 1435-1443.

Meier C, Hoeller S, Bourgau C, Hirschmann P, Schwaller J, Went P, Pileri SA, Reiter A, Dirnhofer S & Tzankov A 2009 Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas. Mod Pathol 22 476-487.

Paulson M, Pisharody S, Pan L, Guadagno S, Mui AL & Levy DE 1999 Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J Biol Chem 274 25343-25349.

Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP & Gilliland DG 2006 Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood 108 1339-1345.

Seidel H, Milocco L, Lamb P, Darnell JJ, Stein R & Rosen J 1995 Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. Proc Natl Acad Sci USA 92 3041-3045.

Torrero MN, Xia X, Henk W, Yu S & Li S 2006 Stat1 deficiency in the host enhances interleukin-12-mediated tumor regression. Cancer Res 66 4461-4467.

van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL, Nordeen SK, Miller GJ & Lucia MS 2003 Molecular characterization of human prostate carcinoma cell lines. Prostate 57 205-225.

Wegenka UM, Buschmann J, Lutticken C, Heinrich PC & Horn F 1993 Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol Cell Biol 13 276-288.

Wiederkehr-Adam M, Ernst P, Müller K, Bieck E, Gombert FO, Ottl J, Graff P, Grossmüller F & Heim MH 2003 Characterization of Phosphopeptide Motifs Specific for the Src Homology 2 Domains of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3. J Biol Chem 278 16117-16128.

Zhong M, Henriksen MA, Takeuchi K, Schaefer O, Liu B, ten Hoeve J, Ren Z, Mao X, Chen X, Shuai K & Darnell JE Jr 2005 Implications of an antiparallel dimeric structure of nonphosphorylated STAT1 for the activation-inactivation cycle. Proc Natl Acad Sci U S A 102 3966-3971.

Zhong Z, Wen Z & Darnell JE Jr 1994 Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science, 264 95-98.

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