Temporally designed treatment of melanoma cells by ATRA and polyI: C results in enhanced chemokine and IFNβ secretion controlled differently by TLR3 and MDA5

Attila Szabo, Rolah M. Osman, Ildiko Bacskai, Brahma V. Kumar, Zsofia Agod, A. Lányi, P. Gogolák, E. Rajnavolgyi

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

In the last three decades, the incidence of melanoma has increased worldwide and no effective treatment modalities have been developed yet. All-trans retinoic acid (ATRA) and polyinosinic:polycytidylic acid (polyI:C) are strong inducers of toll-like receptor 3 (TLR3) and MDA5 expression, and polyI:C-induced TLR3 and MDA5 signaling specifically causes cell death in melanoma cells in vitro. We addressed the question of whether ATRA pretreatment could enhance the efficacy of polyI:C and, if so, would ATRA have any additional effects on this process. We found that the combined treatment of human melanoma cells with ATRA and polyI:C strongly increased the expression of TLR3 and MDA5 in both WM35 and WM983A cells associated with significantly higher mRNA and secreted levels of interferon β (IFNβ), CXCL1, CXCL8/IL-8, CXCL9, and CXCL10 than cells treated with either ATRA or polyI:C. Silencing of MDA5 by siRNA moderately affected IFNβ secretion, whereas TLR3 knockdown interfered with both CXCL chemokine and IFNβ production. Furthermore, the supernatants of ATRA+polyI:C-activated cultures increased the migration of both human monocyte-derived macrophages and CD1a dendritic cells significantly as compared with the supernatants of cells treated with either ATRA or polyI:C, and this effect occurred in a TLR3-dependent manner. In conclusion, consecutive treatment with ATRA and polyI:C results in strong, TLR3/MDA5-mediated chemokine and IFN responses in cultured human melanoma cells, which triggers a functional migratory response in professional antigen-presenting cells. This novel mode of concomitant activation may represent a more efficient treatment option for future melanoma therapy.

Original languageEnglish
Pages (from-to)351-361
Number of pages11
JournalMelanoma Research
Volume22
Issue number5
DOIs
Publication statusPublished - Oct 2012

Fingerprint

Toll-Like Receptor 3
Poly I-C
Tretinoin
Chemokines
Interferons
Melanoma
Antigen-Presenting Cells
Interleukin-8
Dendritic Cells
Small Interfering RNA
Cause of Death
Cell Death
Macrophages
Messenger RNA

Keywords

  • chemokines
  • MDA5
  • toll-like receptor 3
  • type I interferon

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Dermatology

Cite this

Temporally designed treatment of melanoma cells by ATRA and polyI : C results in enhanced chemokine and IFNβ secretion controlled differently by TLR3 and MDA5. / Szabo, Attila; Osman, Rolah M.; Bacskai, Ildiko; Kumar, Brahma V.; Agod, Zsofia; Lányi, A.; Gogolák, P.; Rajnavolgyi, E.

In: Melanoma Research, Vol. 22, No. 5, 10.2012, p. 351-361.

Research output: Contribution to journalArticle

@article{42cdc5c4f6874369ac8bee7f2300974f,
title = "Temporally designed treatment of melanoma cells by ATRA and polyI: C results in enhanced chemokine and IFNβ secretion controlled differently by TLR3 and MDA5",
abstract = "In the last three decades, the incidence of melanoma has increased worldwide and no effective treatment modalities have been developed yet. All-trans retinoic acid (ATRA) and polyinosinic:polycytidylic acid (polyI:C) are strong inducers of toll-like receptor 3 (TLR3) and MDA5 expression, and polyI:C-induced TLR3 and MDA5 signaling specifically causes cell death in melanoma cells in vitro. We addressed the question of whether ATRA pretreatment could enhance the efficacy of polyI:C and, if so, would ATRA have any additional effects on this process. We found that the combined treatment of human melanoma cells with ATRA and polyI:C strongly increased the expression of TLR3 and MDA5 in both WM35 and WM983A cells associated with significantly higher mRNA and secreted levels of interferon β (IFNβ), CXCL1, CXCL8/IL-8, CXCL9, and CXCL10 than cells treated with either ATRA or polyI:C. Silencing of MDA5 by siRNA moderately affected IFNβ secretion, whereas TLR3 knockdown interfered with both CXCL chemokine and IFNβ production. Furthermore, the supernatants of ATRA+polyI:C-activated cultures increased the migration of both human monocyte-derived macrophages and CD1a dendritic cells significantly as compared with the supernatants of cells treated with either ATRA or polyI:C, and this effect occurred in a TLR3-dependent manner. In conclusion, consecutive treatment with ATRA and polyI:C results in strong, TLR3/MDA5-mediated chemokine and IFN responses in cultured human melanoma cells, which triggers a functional migratory response in professional antigen-presenting cells. This novel mode of concomitant activation may represent a more efficient treatment option for future melanoma therapy.",
keywords = "chemokines, MDA5, toll-like receptor 3, type I interferon",
author = "Attila Szabo and Osman, {Rolah M.} and Ildiko Bacskai and Kumar, {Brahma V.} and Zsofia Agod and A. L{\'a}nyi and P. Gogol{\'a}k and E. Rajnavolgyi",
year = "2012",
month = "10",
doi = "10.1097/CMR.0b013e328357076c",
language = "English",
volume = "22",
pages = "351--361",
journal = "Melanoma Research",
issn = "0960-8931",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Temporally designed treatment of melanoma cells by ATRA and polyI

T2 - C results in enhanced chemokine and IFNβ secretion controlled differently by TLR3 and MDA5

AU - Szabo, Attila

AU - Osman, Rolah M.

AU - Bacskai, Ildiko

AU - Kumar, Brahma V.

AU - Agod, Zsofia

AU - Lányi, A.

AU - Gogolák, P.

AU - Rajnavolgyi, E.

PY - 2012/10

Y1 - 2012/10

N2 - In the last three decades, the incidence of melanoma has increased worldwide and no effective treatment modalities have been developed yet. All-trans retinoic acid (ATRA) and polyinosinic:polycytidylic acid (polyI:C) are strong inducers of toll-like receptor 3 (TLR3) and MDA5 expression, and polyI:C-induced TLR3 and MDA5 signaling specifically causes cell death in melanoma cells in vitro. We addressed the question of whether ATRA pretreatment could enhance the efficacy of polyI:C and, if so, would ATRA have any additional effects on this process. We found that the combined treatment of human melanoma cells with ATRA and polyI:C strongly increased the expression of TLR3 and MDA5 in both WM35 and WM983A cells associated with significantly higher mRNA and secreted levels of interferon β (IFNβ), CXCL1, CXCL8/IL-8, CXCL9, and CXCL10 than cells treated with either ATRA or polyI:C. Silencing of MDA5 by siRNA moderately affected IFNβ secretion, whereas TLR3 knockdown interfered with both CXCL chemokine and IFNβ production. Furthermore, the supernatants of ATRA+polyI:C-activated cultures increased the migration of both human monocyte-derived macrophages and CD1a dendritic cells significantly as compared with the supernatants of cells treated with either ATRA or polyI:C, and this effect occurred in a TLR3-dependent manner. In conclusion, consecutive treatment with ATRA and polyI:C results in strong, TLR3/MDA5-mediated chemokine and IFN responses in cultured human melanoma cells, which triggers a functional migratory response in professional antigen-presenting cells. This novel mode of concomitant activation may represent a more efficient treatment option for future melanoma therapy.

AB - In the last three decades, the incidence of melanoma has increased worldwide and no effective treatment modalities have been developed yet. All-trans retinoic acid (ATRA) and polyinosinic:polycytidylic acid (polyI:C) are strong inducers of toll-like receptor 3 (TLR3) and MDA5 expression, and polyI:C-induced TLR3 and MDA5 signaling specifically causes cell death in melanoma cells in vitro. We addressed the question of whether ATRA pretreatment could enhance the efficacy of polyI:C and, if so, would ATRA have any additional effects on this process. We found that the combined treatment of human melanoma cells with ATRA and polyI:C strongly increased the expression of TLR3 and MDA5 in both WM35 and WM983A cells associated with significantly higher mRNA and secreted levels of interferon β (IFNβ), CXCL1, CXCL8/IL-8, CXCL9, and CXCL10 than cells treated with either ATRA or polyI:C. Silencing of MDA5 by siRNA moderately affected IFNβ secretion, whereas TLR3 knockdown interfered with both CXCL chemokine and IFNβ production. Furthermore, the supernatants of ATRA+polyI:C-activated cultures increased the migration of both human monocyte-derived macrophages and CD1a dendritic cells significantly as compared with the supernatants of cells treated with either ATRA or polyI:C, and this effect occurred in a TLR3-dependent manner. In conclusion, consecutive treatment with ATRA and polyI:C results in strong, TLR3/MDA5-mediated chemokine and IFN responses in cultured human melanoma cells, which triggers a functional migratory response in professional antigen-presenting cells. This novel mode of concomitant activation may represent a more efficient treatment option for future melanoma therapy.

KW - chemokines

KW - MDA5

KW - toll-like receptor 3

KW - type I interferon

UR - http://www.scopus.com/inward/record.url?scp=84866242485&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866242485&partnerID=8YFLogxK

U2 - 10.1097/CMR.0b013e328357076c

DO - 10.1097/CMR.0b013e328357076c

M3 - Article

C2 - 22797253

AN - SCOPUS:84866242485

VL - 22

SP - 351

EP - 361

JO - Melanoma Research

JF - Melanoma Research

SN - 0960-8931

IS - 5

ER -