Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations

Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations

The activity of the M isoform of microphthalmia-associated transcription factor (MITF-M) has been attributed to regulation of differentiation, proliferation, survival and senescence of melanoma cells. MITF expression was shown to be antagonized by the activation of transcription factor NF-κB. Parthe...

Full description

Bibliographic Details
Main Authors: Hartman, Mariusz L., Talar, Beata, Sztiller-Sikorska, Malgorzata, Nejc, Dariusz, Czyz, Malgorzata
Format: Online
Language:English
Published: Impact Journals LLC 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891023/
id pubmed-4891023
recordtype oai_dc
spelling pubmed-48910232016-06-20 Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations Hartman, Mariusz L. Talar, Beata Sztiller-Sikorska, Malgorzata Nejc, Dariusz Czyz, Malgorzata Research Paper The activity of the M isoform of microphthalmia-associated transcription factor (MITF-M) has been attributed to regulation of differentiation, proliferation, survival and senescence of melanoma cells. MITF expression was shown to be antagonized by the activation of transcription factor NF-κB. Parthenolide, an inhibitor of NF-κB, has not been yet reported to affect MITF-M expression. Our results obtained in patient-derived melanoma cell populations indicate that parthenolide efficiently decreases the MITF-M level. This is neither dependent on p65/NF-κB signaling nor RAF/MEK/ERK pathway activity as inhibition of MEK by GSK1120212 (trametinib) and induction of ERK1/2 activity by parthenolide itself do not interfere with parthenolide-triggered depletion of MITF-M in both wild-type BRAF and BRAFV600E melanoma populations. Parthenolide activity is not prevented by inhibitors of caspases, proteasomal and lysosomal pathways. As parthenolide reduces MITF-M transcript level and HDAC1 protein level, parthenolide-activated depletion of MITF-M protein may be considered as a result of transcriptional regulation, however, the influence of parthenolide on other elements of a dynamic control over MITF-M cannot be ruled out. Parthenolide induces diverse effects in melanoma cells, from death to senescence. The mode of the response to parthenolide is bound to the molecular characteristics of melanoma cells, particularly to the basal MITF-M expression level but other cell-autonomous differences such as NF-κB activity and MCL-1 level might also contribute. Our data suggest that parthenolide can be developed as a drug used in combination therapy against melanoma when simultaneous inhibition of MITF-M, NF-κB and HDAC1 is needed. Impact Journals LLC 2016-01-27 /pmc/articles/PMC4891023/ /pubmed/26824319 http://dx.doi.org/10.18632/oncotarget.7030 Text en Copyright: © 2016 Hartman et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Hartman, Mariusz L.
Talar, Beata
Sztiller-Sikorska, Malgorzata
Nejc, Dariusz
Czyz, Malgorzata
spellingShingle Hartman, Mariusz L.
Talar, Beata
Sztiller-Sikorska, Malgorzata
Nejc, Dariusz
Czyz, Malgorzata
Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations
author_facet Hartman, Mariusz L.
Talar, Beata
Sztiller-Sikorska, Malgorzata
Nejc, Dariusz
Czyz, Malgorzata
author_sort Hartman, Mariusz L.
title Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations
title_short Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations
title_full Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations
title_fullStr Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations
title_full_unstemmed Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations
title_sort parthenolide induces mitf-m downregulation and senescence in patient-derived mitf-mhigh melanoma cell populations
description The activity of the M isoform of microphthalmia-associated transcription factor (MITF-M) has been attributed to regulation of differentiation, proliferation, survival and senescence of melanoma cells. MITF expression was shown to be antagonized by the activation of transcription factor NF-κB. Parthenolide, an inhibitor of NF-κB, has not been yet reported to affect MITF-M expression. Our results obtained in patient-derived melanoma cell populations indicate that parthenolide efficiently decreases the MITF-M level. This is neither dependent on p65/NF-κB signaling nor RAF/MEK/ERK pathway activity as inhibition of MEK by GSK1120212 (trametinib) and induction of ERK1/2 activity by parthenolide itself do not interfere with parthenolide-triggered depletion of MITF-M in both wild-type BRAF and BRAFV600E melanoma populations. Parthenolide activity is not prevented by inhibitors of caspases, proteasomal and lysosomal pathways. As parthenolide reduces MITF-M transcript level and HDAC1 protein level, parthenolide-activated depletion of MITF-M protein may be considered as a result of transcriptional regulation, however, the influence of parthenolide on other elements of a dynamic control over MITF-M cannot be ruled out. Parthenolide induces diverse effects in melanoma cells, from death to senescence. The mode of the response to parthenolide is bound to the molecular characteristics of melanoma cells, particularly to the basal MITF-M expression level but other cell-autonomous differences such as NF-κB activity and MCL-1 level might also contribute. Our data suggest that parthenolide can be developed as a drug used in combination therapy against melanoma when simultaneous inhibition of MITF-M, NF-κB and HDAC1 is needed.
publisher Impact Journals LLC
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891023/
_version_ 1613588037668700160

Similar Items