CoChat
Sign Up
Cited by 25Cytokine Signaling Pathways and InteractionsDNA and Nucleic Acid ChemistryAdvanced biosensing and bioanalysis techniques

STAT3 inhibition in prostate and pancreatic cancer lines by STAT3 binding sequence oligonucleotides: differential activity between 5′ and 3′ ends

Open access
Lewis, H. Dan, Winter, Ashley, Murphy, Thomas F., Tripathi, Snehlata, Pandey, Virendra N., Barton, Beverly E.·2008·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-08-0154PMC PMC2561307
Open this paper in CoChat — free accountOpen PDF

Abstract

Signal transducers and activators of transcription (STAT) were originally discovered as components of signal transduction pathways. Persistent aberrant activation of STAT3 is a feature of many malignancies including prostate cancer and pancreatic cancer. One consequence of persistently activated STAT3 in malignant cells is that they depend on it for survival; thus, STAT3 is an excellent molecular target for therapy. 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. Here, we report that authentic STAT3 binding sequences, identified from published literature, were more effective for inducing apoptosis in prostate cancer cells and pancreatic cancer cells than was oligonucleotide 13410. Moreover, the authentic STAT3 binding sequences showed differing efficacies in the malignant cell lines depending on whether the canonical STAT3 binding sequence was truncated at the 5′ or the 3′ end. Finally, expression of one STAT3-regulated gene was decreased following treatment, suggesting that STAT3 may regulate the same set of genes in the two types of cancer. We conclude that truncating the 5′ end left intact enough of the canonical STAT3 binding site for effective hybridization to the genome, whereas truncation of the 3′ end, which is outside the canonical binding site, may have affected binding of required cofactors essential for STAT3 activity, thereby reducing the capacity of this modified oligonucleotide to induce apoptosis. Additional experiments to answer this hypothesis are under way. [Mol Cancer Ther 2008;7(6):1543–50]

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/1535-7163.mct-08-0154

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Nucleic acid-based drugs, including decoy oligonucleotides and, perhaps, G-quartet oligonucleotides, inhibit STAT3-mediated gene expression and inhibit growth of different cancer cell lines.

    “Nucleic acid–based drugs, including decoy oligonucleotides and, perhaps, G-quartet oligonucleotides, have been identified that inhibit STAT3-mediated gene expression and inhibit growth of different cancer cell lines (Leong et al., 2003; Lewis et al., 2008; Sun et al., 2008; Shen et al., 2009; Zhang et al., 2013b; Liu et al., 2014; Sen et al., 2014).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Lewis et al., 2008

    The Abstract reports that STAT3-binding-sequence oligonucleotides induced apoptosis in prostate and pancreatic cancer cell lines. The section ‘Anti-STAT3 Oligonucleotides Inhibited Expression of a STAT3-Regulated Gene, CD46’ reports reduced CD46 expression, supporting the gene-expression part of the claim. This paper does not establish the claim about G-quartet oligonucleotides. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 38

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43 -66.
  2. Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781 -9.
  3. Cooperberg MR, Grossfeld GD, Lubeck DP, Carroll PR. National practice patterns and time trends in androgen ablation for localized prostate cancer. J Natl Cancer Inst 2003;95:981 -9.
  4. Xie K, Wei D, Huang S. Transcriptional anti-angiogenesis therapy of human pancreatic cancer. Cytokine Growth Factor Rev 2006;17:147- 56.
  5. Ihle JN. STATs and MAPKs: obligate or opportunistic partners in signaling. BioEssays 1996;18:95 -8.
  6. Grandis JR, Drenning SD, Chakraborty A, et al. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro . J Clin Invest 1998;102:1385 -92.
  7. Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999;10:105 -15.
  8. Barton BE, Murphy TF, Adem P, Watson RA, Irwin RJ, Huang HS. 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 2001;1:19.
  9. Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 2001;107:351 -62.
  10. van Bokhoven A, Varella-Garcia M, Korch C, et al. Molecular character- ization of human prostate carcinoma cell lines. Prostate 2003;57:205 -25.
  11. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 2002;8:945 -54.
  12. Barton BE, Karras JG, Murphy TF, Barton AB, Huang HF. STAT3 activation in prostate cancer: direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther 2004;3:11 -20.
  13. Seidel H, Milocco L, Lamb P, Darnell JJ, Stein R, Rosen J. 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 U S A 1995;92:3041 -5.
  14. Zhong M, Henriksen MA, Takeuchi K, et al. Implications of an antiparallel dimeric structure of nonphosphorylated STAT1 for the activation-inactivation cycle. Proc Natl Acad Sci U S A 2005;102:3966-71.
  15. Zhong Z, Wen Z, Darnell JE, Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994;264:95 -8.
  16. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell 1999;98:295 -3-3.
  17. Gursel I, Gursel M, Yamada H, Ishii KJ, Takeshita F, Klinman DM. Repetitive elements in mammalian telomeres suppress bacterial DNA- induced immune activation. J Immunol 2003;171:1393 -400.
  18. Barton BE, Murphy TF, Shu P, Huang HF, Meyenhofen M, Barton AB. Novel single-stranded oligonucleotides that inhibit STAT3 induce apop- tosis in vitro and in vivo in prostate cancer cell lines. Mol Cancer Ther 2004;3: 3:1183 -91.
  19. Guvakova MA, Yakubov LA, Vlodavesky I, Tonkinson JL, Stein CA. 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 1995;270:2620 -7.
  20. Goethe JW, Bittova M, Vogel JU, Kotchekov R, Doerr HW, Cinati J, Jr. Antisense oligonucleotide ISIS 2922 targets IE-expression and prevents HCMV-IE-induced suppression of TSP-1 and TSP-2 expression. Nucleosides Nucleotides Nucleic Acids 2001;20:1425 -8.
  21. Venkatasubbarao K, Choudary A, Freeman JW. Farnesyl transferase inhibitor (R115777)-induced inhibition of STAT3(Tyr 705 ) phosphorylation in human pancreatic cancer cell lines require extracellular signal-regulated kinases. Cancer Res 2005;65:2861 -71.
  22. DeArmond D, Brattain MG, Jessup JM, et al. Autocrine-mediated ErbB- 2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. Oncogene 2003;22:7781 -95.
  23. Hayward SW, Wang Y, Cao M, et al. Malignant transformation in a non- tumorigenic prostatic epithelial cell line. Cancer Res 2001;61:8135 -42.
  24. Rushmere NK, Knowlden JM, Gee JMW, et al. Analysis of the level of mRNA expression of the membrane regulators of complement, CD59, CD55, and CD46, in breast cancer. Int J Cancer 2004;108:930 -6.
  25. Danielpour D. Transdifferentiation of NRP-152 rat prostatic basal epithelial cells toward a luminal phenotype: regulation by glucocorticoid, insulin-like growth factor-I and transforming growth factor-h. J Cell Sci 1998;112:169 -79.
  26. Lucia MS, Sporn MB, Roberts AB, Stewart LV, Danielpour D. The role of transforming growth factor-b1, -b2, -b3 in androgen-responsive growth of NRP-152 rat prostatic epithelial cells. J Cell Phys 1998;175:184 -92.
  27. Wang Y, Sudlivsky D, Zhang B, et al. A human prostatic epithelial model of hormonal carcinogenesis. Cancer Res 2001;61:6064 -71.
  28. Buettner R, Huang M, Gritsko T, et al. Activated signal transducers and activators of transcription 3 signaling induces CD46 expression and protects human cancer cells from complement-dependent cytotoxicity. Mol Cancer Res 2007;5:823 -32.
  29. Culig Z, Comuzzi B, Steiner H, Bartsch G, Hobisch A. Expression and function of androgen receptor coactivators in prostate cancer. J Steroid Biochem Mol Biol 2004;92:265 -71.
  30. Wallner L, Dai J, Escara-Wilke J, et al. Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen- independent phenotype in orchiectomized mice. Cancer Res 2006;66: 3087 -95.
  31. Barre B, Avril S, Coqueret O. Opposite regulation of Myc and p21 waf1 transcription by STAT3 proteins. J Biol Chem 2003;278:2990 -6.
  32. Joo A, Aburuatani H, Morii E, Iba H, Yoshimura A. STAT3 and MITF cooperatively induce cellular transformation through upregulation of c-fos expression. Oncogene 2004;23:726 -34.
  33. Levy DE, Lee C-k. What does Stat3 do? J Clin Invest 2002;109: 1143 -8.
  34. Paulson M, Pisharody S, Pan L, Guadagno S, Mui AL, Levy DE. Stat protein transactivation domains recruit p300/CBP through widely diver- gent sequences. J Biol Chem 1999;274:25343 -9.
  35. Koppelhus U, Nielsen PE. Cellular delivery of peptide nucleic acid (PNA). Adv Drug Deliv Rev 2003;55:267 -80.
  36. Nielsen PE. Addressing the challenges of cellular delivery and bioavailability of peptide nucleic acids (PNA). Quarterly Rev Biophys 2006;38:345 -50.
  37. Mae M, Langel U. Cell-penetrating peptides as vectors for pep- tide, protein and oligonucleotide delivery. Curr Opin Pharmacol 2006;6: 509 -14.
  38. Zhilina ZV, Ziemba AJ, Nielsen PE, Ebbinghaus SW. PNA-nitrogen mustard conjugates are effective suppressors of HER-2/neu and biological tools for recognition of PNA/DNA interactions. Bioconjug Chem 2006;17: 214 -22.

Cited by

Sorted by citations

Authors
Lewis, H. D., Winter, A., Murphy, T. F., Tripathi, S., Pandey, V. N., & Barton, B. E.
Affiliations
  • 1Surgery, and Departments of
  • Rutgers New Jersey Medical School (US)
  • VA New Jersey Health Care System (US)
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2008-06-01
Volume
7
Issue
6
Pages
1543-1550
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-08-0154
PMC
PMC2561307
OpenAlex
W2162692965
Cited by
25
References
1
Citations by year
2026: 1 · 2024: 1 · 2020: 1 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 1 · 2012: 4
FWCI
1.41
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • National Institutes of Health
  • National Cancer Institute (CA 121782, R21CA121782)
  • National Institute of Allergy and Infectious Diseases (AI142529)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
Keywords
STAT3, prostate cancer, pancreatic cancer, antisense oligonucleotides, oligonucleotide design, apoptosis induction, gene silencing
MeSH terms
Base Sequence, Humans, Male, Molecular Sequence Data, Oligonucleotides, Oxidation-Reduction, Pancreatic Neoplasms, Prostatic Neoplasms, Protein Binding, Gene Expression Regulation, Neoplastic, Apoptosis, Cell Line, Tumor, STAT3 Transcription Factor, Membrane Cofactor Protein

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review