RIG-inhibits the MAPK-dependent proliferation of BRAF mutant melanoma cells via MKP-1

Attila Szabo, Tunde Fekete, G. Koncz, Brahma V. Kumar, Kitti Pazmandi, Zsofia Foldvari, B. Hegedűs, Tamas Garay, Attila Bacsi, E. Rajnavolgyi, A. Lányi

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: BRAF-mutant melanoma is characterized by aggressive metastatic potential and therapeutic resistance. The innate immune receptor RIG-has emerged as a potential target in melanoma therapies but the contributing pathways involved in anti-cancer activity are poorly characterized. Methods: Baseline and ATRA-induced expression of RIG-in nine (wild type and 6 BRAF-mutant) melanoma cell lines was measured with Q-PCR and Western blot. Ligand-specific stimulation of RIG-was detected by Q-PCR and ELISA. Activation of the RIG-I-coupled IRF3, NF-κB and MAPK pathways was tested with protein array and Western blot. Cell proliferation and apoptosis was monitored by flow cytometry and cell counting. Down modulation of MKP-expression in melanoma cells was performed by specific siRNA. Results: Short-term ATRA pre-treatment increases the expression of RIG-in BRAF-mutant melanoma cells. Specific activation of RIG-by 5[U+02B9]ppp-dsRNA leads to increased activity of the IRF3-IFNβ pathway but does not influence NF-κB signaling. RIG-mediates the targeted dephosphorylation of several MAPKs (p38, RSK1, GSK-3α/β, HSP27) via the endogenous regulator MKP-resulting in decreased melanoma cell proliferation. Conclusion: RIG-has the potential to exert anticancer activity in BRAF-mutant melanoma via controlling IFNβ production and MAPK signaling. This is the first study showing that RIG-activation results in MKP-1-mediated inhibition of cell proliferation via controlling the p38-HSP27, c-Jun and rpS6 pathways thus identifying RIG-and MKP-as novel and promising therapeutical targets.

Original languageEnglish
Pages (from-to)335-347
Number of pages13
JournalCellular Signalling
Volume28
Issue number5
DOIs
Publication statusPublished - May 1 2016

Fingerprint

Melanoma
Cell Proliferation
Western Blotting
Glycogen Synthase Kinase 3
Polymerase Chain Reaction
Protein Array Analysis
p38 Mitogen-Activated Protein Kinases
Small Interfering RNA
Flow Cytometry
Therapeutics
Enzyme-Linked Immunosorbent Assay
Apoptosis
Ligands
Cell Line
Neoplasms

Keywords

  • BRAF
  • MAPK
  • Melanoma
  • MKP-1/DUSP1
  • Proliferation
  • RIG-I

ASJC Scopus subject areas

  • Cell Biology

Cite this

RIG-inhibits the MAPK-dependent proliferation of BRAF mutant melanoma cells via MKP-1. / Szabo, Attila; Fekete, Tunde; Koncz, G.; Kumar, Brahma V.; Pazmandi, Kitti; Foldvari, Zsofia; Hegedűs, B.; Garay, Tamas; Bacsi, Attila; Rajnavolgyi, E.; Lányi, A.

In: Cellular Signalling, Vol. 28, No. 5, 01.05.2016, p. 335-347.

Research output: Contribution to journalArticle

Szabo, Attila ; Fekete, Tunde ; Koncz, G. ; Kumar, Brahma V. ; Pazmandi, Kitti ; Foldvari, Zsofia ; Hegedűs, B. ; Garay, Tamas ; Bacsi, Attila ; Rajnavolgyi, E. ; Lányi, A. / RIG-inhibits the MAPK-dependent proliferation of BRAF mutant melanoma cells via MKP-1. In: Cellular Signalling. 2016 ; Vol. 28, No. 5. pp. 335-347.
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abstract = "Background: BRAF-mutant melanoma is characterized by aggressive metastatic potential and therapeutic resistance. The innate immune receptor RIG-has emerged as a potential target in melanoma therapies but the contributing pathways involved in anti-cancer activity are poorly characterized. Methods: Baseline and ATRA-induced expression of RIG-in nine (wild type and 6 BRAF-mutant) melanoma cell lines was measured with Q-PCR and Western blot. Ligand-specific stimulation of RIG-was detected by Q-PCR and ELISA. Activation of the RIG-I-coupled IRF3, NF-κB and MAPK pathways was tested with protein array and Western blot. Cell proliferation and apoptosis was monitored by flow cytometry and cell counting. Down modulation of MKP-expression in melanoma cells was performed by specific siRNA. Results: Short-term ATRA pre-treatment increases the expression of RIG-in BRAF-mutant melanoma cells. Specific activation of RIG-by 5[U+02B9]ppp-dsRNA leads to increased activity of the IRF3-IFNβ pathway but does not influence NF-κB signaling. RIG-mediates the targeted dephosphorylation of several MAPKs (p38, RSK1, GSK-3α/β, HSP27) via the endogenous regulator MKP-resulting in decreased melanoma cell proliferation. Conclusion: RIG-has the potential to exert anticancer activity in BRAF-mutant melanoma via controlling IFNβ production and MAPK signaling. This is the first study showing that RIG-activation results in MKP-1-mediated inhibition of cell proliferation via controlling the p38-HSP27, c-Jun and rpS6 pathways thus identifying RIG-and MKP-as novel and promising therapeutical targets.",
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T1 - RIG-inhibits the MAPK-dependent proliferation of BRAF mutant melanoma cells via MKP-1

AU - Szabo, Attila

AU - Fekete, Tunde

AU - Koncz, G.

AU - Kumar, Brahma V.

AU - Pazmandi, Kitti

AU - Foldvari, Zsofia

AU - Hegedűs, B.

AU - Garay, Tamas

AU - Bacsi, Attila

AU - Rajnavolgyi, E.

AU - Lányi, A.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Background: BRAF-mutant melanoma is characterized by aggressive metastatic potential and therapeutic resistance. The innate immune receptor RIG-has emerged as a potential target in melanoma therapies but the contributing pathways involved in anti-cancer activity are poorly characterized. Methods: Baseline and ATRA-induced expression of RIG-in nine (wild type and 6 BRAF-mutant) melanoma cell lines was measured with Q-PCR and Western blot. Ligand-specific stimulation of RIG-was detected by Q-PCR and ELISA. Activation of the RIG-I-coupled IRF3, NF-κB and MAPK pathways was tested with protein array and Western blot. Cell proliferation and apoptosis was monitored by flow cytometry and cell counting. Down modulation of MKP-expression in melanoma cells was performed by specific siRNA. Results: Short-term ATRA pre-treatment increases the expression of RIG-in BRAF-mutant melanoma cells. Specific activation of RIG-by 5[U+02B9]ppp-dsRNA leads to increased activity of the IRF3-IFNβ pathway but does not influence NF-κB signaling. RIG-mediates the targeted dephosphorylation of several MAPKs (p38, RSK1, GSK-3α/β, HSP27) via the endogenous regulator MKP-resulting in decreased melanoma cell proliferation. Conclusion: RIG-has the potential to exert anticancer activity in BRAF-mutant melanoma via controlling IFNβ production and MAPK signaling. This is the first study showing that RIG-activation results in MKP-1-mediated inhibition of cell proliferation via controlling the p38-HSP27, c-Jun and rpS6 pathways thus identifying RIG-and MKP-as novel and promising therapeutical targets.

AB - Background: BRAF-mutant melanoma is characterized by aggressive metastatic potential and therapeutic resistance. The innate immune receptor RIG-has emerged as a potential target in melanoma therapies but the contributing pathways involved in anti-cancer activity are poorly characterized. Methods: Baseline and ATRA-induced expression of RIG-in nine (wild type and 6 BRAF-mutant) melanoma cell lines was measured with Q-PCR and Western blot. Ligand-specific stimulation of RIG-was detected by Q-PCR and ELISA. Activation of the RIG-I-coupled IRF3, NF-κB and MAPK pathways was tested with protein array and Western blot. Cell proliferation and apoptosis was monitored by flow cytometry and cell counting. Down modulation of MKP-expression in melanoma cells was performed by specific siRNA. Results: Short-term ATRA pre-treatment increases the expression of RIG-in BRAF-mutant melanoma cells. Specific activation of RIG-by 5[U+02B9]ppp-dsRNA leads to increased activity of the IRF3-IFNβ pathway but does not influence NF-κB signaling. RIG-mediates the targeted dephosphorylation of several MAPKs (p38, RSK1, GSK-3α/β, HSP27) via the endogenous regulator MKP-resulting in decreased melanoma cell proliferation. Conclusion: RIG-has the potential to exert anticancer activity in BRAF-mutant melanoma via controlling IFNβ production and MAPK signaling. This is the first study showing that RIG-activation results in MKP-1-mediated inhibition of cell proliferation via controlling the p38-HSP27, c-Jun and rpS6 pathways thus identifying RIG-and MKP-as novel and promising therapeutical targets.

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KW - MAPK

KW - Melanoma

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KW - Proliferation

KW - RIG-I

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