CoChat
Sign Up
Cited by 69Immune Response and InflammationImmunotherapy and Immune ResponsesCancer-related Molecular Pathways

TLR3 induction by anticancer drugs potentiates poly I:C-induced tumor cell apoptosis

Open access
Taura, Manabu, Fukuda, Ryosuke, Suico, Mary Ann, Eguma, Ayaka, Koga, Tomoaki, Shuto, Tsuyoshi, Sato, Takashi, Morino‐Koga, Saori +1 more·2010·Cancer Science
DOI 10.1111/j.1349-7006.2010.01567.xPMC PMC11159143
Open this paper in CoChat — free account

Abstract

Toll-like receptor 3 (TLR3) has gained recognition as a novel molecular target for cancer therapy because TLR3 activation by its synthetic ligand poly I:C directly causes tumor cell death. Recently, we reported that tumor suppressor p53 increases the expression of TLR3 in several tumor cell lines. Another study also showed that interferon-alpha (IFN-alpha) up-regulates TLR3 expression. We thus hypothesized that various anticancer drugs such as p53-activating reagents and IFNs may potentiate poly I:C-induced tumor cell death through the up-regulation of TLR3 expression. Here, we screened several anticancer drugs that, together with poly I:C, effectively cause tumor cell death in colon carcinoma HCT116 cells. We found that the DNA-damaging reagent 5-fluorouracil (5-FU) increased TLR3 mRNA expression and potentiated poly I:C-induced apoptosis in HCT116 p53(+/+) cells but had only minimal effect in p53(-/-) cells, indicating a p53-dependent pathway. On the other hand, IFN-alpha increased poly I:C-induced apoptosis and the TLR3 mRNA level in HCT116 p53(+/+) and p53(-/-) cell lines. Furthermore, the combination of poly I:C, 5-FU and IFN-alpha induced the highest apoptosis in HCT116 p53(+/+) and p53(-/-) cells. Taken together, these data suggest that the anticancer drugs increased TLR3 expression and subsequently potentiated poly I:C-induced apoptosis likely via p53-dependent and -independent pathways. Considering that the p53 status in malignant cells is heterogeneous, this combination approach may provide a highly effective tumor therapy.

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 · 10.1111/j.1349-7006.2010.01567.x

Cites

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?

  • Activation of TLR3 signaling by its agonists can induce apoptosis in human cancer cells.

    “Activation of TLR3 signaling by its agonists can induce apoptosis in human cancer cells [29, 33].”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [29]

  • TLR3 can directly trigger apoptosis in human cancer cells in response to poly(I:C).

    “TLR3 can directly trigger apoptosis in human cancer cells in response to the double-strand RNA synthetic agonist polyinosinic-polycytidylic acid (poly(I:C)) [28, 29], which is a mimic for viral double-stranded RNA that triggers an innate immune response following viral infection.”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [29]

  • Anticancer drugs including 5FU, cisplatin, etoposide, and interferons could increase poly(I:C)-induced cell death in HCT116 cells that are WT p53.

    “Taura et al. [29] reported that anticancer drugs including 5FU, cisplatin, etoposide, and interferons could increase poly(I:C)-induced cell death in HCT116 cells that are WT p53.”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [29]

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

No references could be resolved yet.

Research works printed but not linked: 36

  1. [1]1. Lacour J, Laplanche A, Malafosse M et al. Polyadenylic‐polyuridylic acid as an adjuvant in resectable colorectal carcinoma: a 6 1/2 year follow‐up analysis of a multicentric double blind randomized trial. Eur J Surg Oncol 1992; 18: 599–604. [PubMed] [Google Scholar]
  2. [2]2. Laplanche A, Alzieu L, Delozier T et al. Polyadenylic‐polyuridylic acid plus locoregional radiotherapy versus chemotherapy with CMF in operable breast cancer: a 14 year follow‐up analysis of a randomized trial of the Federation Nationale des Centres de Lutte contre le Cancer (FNCLCC). Breast Cancer Res Treat 2000; 64: 189–91. [DOI] [PubMed] [Google Scholar]
  3. [3]3. Adams M, Navabi H, Croston D et al. The rationale for combined chemo/immunotherapy using a Toll‐like receptor 3 (TLR3) agonist and tumour‐derived exosomes in advanced ovarian cancer. Vaccine 2005; 23: 2374–8. [DOI] [PubMed] [Google Scholar]
  4. [4]4. Le UM, Yanasarn N, Lohr CV, Fischer KA, Cui Z. Tumor chemo‐immunotherapy using gemcitabine and a synthetic dsRNA. Cancer Biol Ther 2008; 7: 440–7. [DOI] [PubMed] [Google Scholar]
  5. [5]5. Salaun B, Lebecque S, Matikainen S, Rimoldi D, Romero P. Toll‐like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res 2007; 13: 4565–74. [DOI] [PubMed] [Google Scholar]
  6. [6]6. Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 2006; 176: 4894–901. [DOI] [PubMed] [Google Scholar]
  7. [7]7. Hickman JA, Potten CS, Merritt AJ, Fisher TC. Apoptosis and cancer chemotherapy. Philos Trans R Soc Lond B Biol Sci 1994; 345: 319–25. [DOI] [PubMed] [Google Scholar]
  8. [8]8. Hurley LH. DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer 2002; 2: 188–200. [DOI] [PubMed] [Google Scholar]
  9. [9]9. Taura M, Eguma A, Suico MA et al. p53 regulates Toll‐like receptor 3 expression and function in human epithelial cell lines. Mol Cell Biol 2008; 28: 6557–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. [10]10. Moschos S, Kirkwood JM. Present role and future potential of type I interferons in adjuvant therapy of high‐risk operable melanoma. Cytokine Growth Factor Rev 2007; 18: 451–8. [DOI] [PubMed] [Google Scholar]
  11. [11]11. Ascierto PA, Kirkwood JM. Adjuvant therapy of melanoma with interferon: lessons of the past decade. J Transl Med 2008; 6: 62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. [12]12. Agarwala SS, Kirkwood JM. Update on the role of adjuvant interferon for high risk melanoma. Forum (Genoa) 2000; 10: 230–9. [PubMed] [Google Scholar]
  13. [13]13. Mills EJ, Rachlis B, O’Regan C, Thabane L, Perri D. Metastatic renal cell cancer treatments: an indirect comparison meta‐analysis. BMC Cancer 2009; 9: 34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. [14]14. Borden EC, Sen GC, Uze G et al. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 2007; 6: 975–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. [15]15. Stark GR. How cells respond to interferons revisited: from early history to current complexity. Cytokine Growth Factor Rev 2007; 18: 419–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. [16]16. Tissari J, Siren J, Meri S, Julkunen I, Matikainen S. IFN‐alpha enhances TLR3‐mediated antiviral cytokine expression in human endothelial and epithelial cells by up‐regulating TLR3 expression. J Immunol 2005; 174: 4289–94. [DOI] [PubMed] [Google Scholar]
  17. [17]17. Sato T, Susuki S, Suico MA et al. Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell. EMBO J 2007; 26: 2501–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. [18]18. Morikawa T, Sugiyama A, Kume H et al. Identification of Toll‐like receptor 3 as a potential therapeutic target in clear cell renal cell carcinoma. Clin Cancer Res 2007; 13: 5703–9. [DOI] [PubMed] [Google Scholar]
  19. [19]19. Klampfer L, Huang J, Kaler P, Sasazuki T, Shirasawa S, Augenlicht L. STAT1‐independent inhibition of cyclooxygenase‐2 expression by IFNgamma; a common pathway of IFNgamma‐mediated gene repression but not gene activation. Oncogene 2007; 26: 2071–81. [DOI] [PubMed] [Google Scholar]
  20. [20]20. Oba M, Yano S, Shuto T, Suico MA, Eguma A, Kai H. IFN‐gamma down‐regulates Hsp27 and enhances hyperthermia‐induced tumor cell death in vitro and tumor suppression in vivo. Int J Oncol 2008; 32: 1317–24. [DOI] [PubMed] [Google Scholar]
  21. [21]21. Suico MA, Yoshida H, Seki Y et al. Myeloid Elf‐1‐like factor, an ETS transcription factor, up‐regulates lysozyme transcription in epithelial cells through interaction with promyelocytic leukemia protein. J Biol Chem 2004; 279: 19091–8. [DOI] [PubMed] [Google Scholar]
  22. [22]22. Morino S, Kondo T, Sasaki K et al. Mild electrical stimulation with heat shock ameliorates insulin resistance via enhanced insulin signaling. PLoS ONE 2008; 3: e4068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [23]23. Vassilev LT, Vu BT, Graves B et al. In vivo activation of the p53 pathway by small‐molecule antagonists of MDM2. Science 2004; 303: 844–8. [DOI] [PubMed] [Google Scholar]
  24. [24]24. Tanabe M, Kurita‐Taniguchi M, Takeuchi K et al. Mechanism of up‐regulation of human Toll‐like receptor 3 secondary to infection of measles virus‐attenuated strains. Biochem Biophys Res Commun 2003; 311: 39–48. [DOI] [PubMed] [Google Scholar]
  25. [25]25. Khvalevsky E, Rivkin L, Rachmilewitz J, Galun E, Giladi H. TLR3 signaling in a hepatoma cell line is skewed towards apoptosis. J Cell Biochem 2007; 100: 1301–12. [DOI] [PubMed] [Google Scholar]
  26. [26]26. Wadler S, Schwartz EL. Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res 1990; 50: 3473–86. [PubMed] [Google Scholar]
  27. [27]27. Wadler S, Wersto R, Weinberg V, Thompson D, Schwartz EL. Interaction of fluorouracil and interferon in human colon cancer cell lines: cytotoxic and cytokinetic effects. Cancer Res 1990; 50: 5735–9. [PubMed] [Google Scholar]
  28. [28]28. Wada H, Nagano H, Noda T et al. Complete remission of hepatocellular carcinoma with portal vein tumor thrombus and lymph node metastases by arterial infusion of 5‐fluorouracil and interferon‐alpha combination therapy following hepatic resection. J Gastroenterol 2007; 42: 501–6. [DOI] [PubMed] [Google Scholar]
  29. [29]29. Wada H, Nagano H, Yamamoto H et al. Combination therapy of interferon‐alpha and 5‐fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins. Oncol Rep 2007; 18: 801–9. [PubMed] [Google Scholar]
  30. [30]30. Koike K, Takaki A, Tatsukawa M et al. Combination of 5‐FU and IFNalpha enhances IFN signaling pathway and caspase‐8 activity, resulting in marked apoptosis in hepatoma cell lines. Int J Oncol 2006; 29: 1253–61. [PubMed] [Google Scholar]
  31. [31]31. Hagiwara S, Kudo M, Nakatani T et al. Combination therapy with PEG‐IFN‐alpha and 5‐FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53. Br J Cancer 2007; 97: 1532–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. [32]32. Greco FA, Figlin R, York M et al. Phase III randomized study to compare interferon alfa‐2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol 1996; 14: 2674–81. [DOI] [PubMed] [Google Scholar]
  33. [33]33. Saltz L, Kemeny N, Schwartz G, Kelsen D. A phase II trial of alpha‐interferon and 5‐fluorouracil in patients with advanced carcinoid and islet cell tumors. Cancer 1994; 74: 958–61. [DOI] [PubMed] [Google Scholar]
  34. [34]34. Hughes MJ, Kerr DJ, Cassidy J et al. A pilot study of combination therapy with interferon‐alpha‐2a and 5‐fluorouracil in metastatic carcinoid and malignant endocrine pancreatic tumours. Ann Oncol 1996; 7: 208–10. [DOI] [PubMed] [Google Scholar]
  35. [35]35. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004; 4: 437–47. [DOI] [PubMed] [Google Scholar]
  36. [36]36. Klein S, McCormick F, Levitzki A. Killing time for cancer cells. Nat Rev Cancer 2005; 5: 573–80. [DOI] [PubMed] [Google Scholar] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article.

Cited by

Sorted by citations

Authors
Taura, M., Fukuda, R., Suico, M. A., Eguma, A., Koga, T., Shuto, T., Sato, T., Morino‐Koga, S., & Kai, H.
Affiliations
Kumamoto University (JP)
Corresponding author
Kai, Hirofumi
ORCID
Venue
Cancer Science
Publisher
Wiley
Published
2010-06-14
Volume
101
Issue
7
Pages
1610-1617
ISSN
  • 1347-9032 (ISSN-L)
  • 1349-7006
DOI
10.1111/j.1349-7006.2010.01567.x
PMC
PMC11159143
OpenAlex
W2005765207
Cited by
69
References
0
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 9 · 2016: 4 · 2015: 4 · 2014: 3 · 2013: 8 · 2012: 7
FWCI
3.44
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Cancer Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
TLR3, poly(I:C), anticancer agents, apoptosis, p53, interferon-alpha, 5-fluorouracil, colon cancer, HCT116 cells, combination therapy
MeSH terms
Adenocarcinoma, Animals, Antineoplastic Agents, Cell Cycle, Cell Line, DNA Damage, Fluorouracil, Humans, Kidney, Lung Neoplasms, Poly I-C, Colorectal Neoplasms, Interferon-alpha, Interferon-beta, Cell Death, Apoptosis, Cell Line, Tumor, Toll-Like Receptor 3, Mice

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