title: Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-M(high) melanoma cell populations.
abstract: 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 BRAF(V600E) 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.
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Mariusz L
authors.initials: ML
authors.lastname: Hartman
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Talar
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Sztiller-Sikorska
authors.affiliation: Department of Surgical Oncology, Medical University of Lodz, Lodz, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Nejc
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Czyz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D051739:Microphthalmia-Associated Transcription Factor; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C498143:RELA protein, human; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; C002669:parthenolide; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: MITF; NF-κB; cellular senescence; melanoma; parthenolide
references.citation: J Immunol. 1999 Nov 15;163(10):5617-23
references.pmid: 10553091
references.citation: Exp Cell Res. 2000 Mar 15;255(2):135-43
references.pmid: 10694430
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: J Biol Chem. 2002 Oct 11;277(41):38954-64
references.pmid: 12151389
references.citation: Pigment Cell Res. 2003 Jun;16(3):261-5
references.pmid: 12753399
references.citation: Carcinogenesis. 2004 Aug;25(8):1449-58
references.pmid: 15033901
references.citation: Invest New Drugs. 2004 Aug;22(3):299-305
references.pmid: 15122077
references.citation: Life Sci. 2004 Jul 2;75(7):841-56
references.pmid: 15183076
references.citation: Oncogene. 2004 Sep 23;23(44):7330-44
references.pmid: 15286701
references.citation: Physiol Rev. 2004 Oct;84(4):1155-228
references.pmid: 15383650
references.citation: Blood. 2005 Jun 1;105(11):4163-9
references.pmid: 15687234
references.citation: Nature. 2005 Jul 7;436(7047):117-22
references.pmid: 16001072
references.citation: Nature. 2005 Aug 4;436(7051):720-4
references.pmid: 16079850
references.citation: Genes Dev. 2005 Sep 1;19(17):1980-5
references.pmid: 16140982
references.citation: Cancer Lett. 2007 Aug 28;254(1):119-27
references.pmid: 17470383
references.citation: Chem Biol. 2007 Jul;14(7):813-23
references.pmid: 17656318
references.citation: Blood. 2007 Dec 15;110(13):4427-35
references.pmid: 17804695
references.citation: Pigment Cell Melanoma Res. 2008 Aug;21(4):457-63
references.pmid: 18627530
references.citation: Mol Cancer Ther. 2009 Mar;8(3):552-62
references.pmid: 19276167
references.citation: Melanoma Res. 2010 Feb;20(1):21-34
references.pmid: 19949351
references.citation: Cell Res. 2009 Dec;19(12):1313-5
references.pmid: 19956183
references.citation: Int J Cancer. 2010 Oct 1;127(7):1625-36
references.pmid: 20099279
references.citation: Prostate. 2010 Jul 1;70(10):1074-86
references.pmid: 20209491
references.citation: Cancer Res. 2010 May 1;70(9):3813-22
references.pmid: 20388797
references.citation: Br J Pharmacol. 2010 Jul;160(5):1144-57
references.pmid: 20590608
references.citation: J Invest Dermatol. 2011 Jun;131(6):1291-9
references.pmid: 21346776
references.citation: J Cell Physiol. 2011 Jun;226(6):1632-41
references.pmid: 21413021
references.citation: Genes Dev. 2011 Jun 15;25(12):1245-61
references.pmid: 21646373
references.citation: J Inflamm (Lond). 2011 Oct 12;8:26
references.pmid: 21992677
references.citation: Nat Rev Cancer. 2012 Jan 19;12(2):121-32
references.pmid: 22257950
references.citation: Mol Cell Biol. 2012 May;32(10):1879-92
references.pmid: 22451485
references.citation: Nat Rev Cancer. 2012 Apr 05;12(5):349-61
references.pmid: 22475929
references.citation: Melanoma Res. 2012 Jun;22(3):215-24
references.pmid: 22495670
references.citation: J Cell Physiol. 2013 May;228(5):952-67
references.pmid: 22688575
references.citation: Cell. 2012 Jul 20;150(2):251-63
references.pmid: 22817889
references.citation: Cancer Prev Res (Phila). 2012 Nov;5(11):1298-309
references.pmid: 23037503
references.citation: Cancer Biol Ther. 2013 Feb;14(2):135-45
references.pmid: 23192276
references.citation: J Invest Dermatol. 2013 Apr;133(4):1063-71
references.pmid: 23223141
references.citation: J Invest Dermatol. 2013 Apr;133(4):1072-9
references.pmid: 23254773
references.citation: Blood. 2013 Feb 21;121(8):1384-93
references.pmid: 23264600
references.citation: J Invest Dermatol. 2013 Jun;133(6):1601-9
references.pmid: 23321925
references.citation: Oncotarget. 2012 Dec;3(12):1522-32
references.pmid: 23455653
references.citation: Cancer Cell. 2013 Mar 18;23(3):302-15
references.pmid: 23477830
references.citation: Drug Discov Today. 2013 Sep;18(17-18):894-905
references.pmid: 23688583
references.citation: Anticancer Drugs. 2013 Sep;24(8):835-45
references.pmid: 23797801
references.citation: Nature. 2013 Dec 5;504(7478):138-42
references.pmid: 24185007
references.citation: J Invest Dermatol. 2014 Jan;134(1):16-17
references.pmid: 24352080
references.citation: PLoS One. 2014 Jan 23;9(1):e86338
references.pmid: 24466036
references.citation: PLoS One. 2014 Mar 03;9(3):e90783
references.pmid: 24595456
references.citation: Mayo Clin Proc. 2014 Apr;89(4):429-33
references.pmid: 24684870
references.citation: PLoS One. 2014 Apr 14;9(4):e95157
references.pmid: 24733089
references.citation: Oncotarget. 2014 Apr 15;5(7):1701-52
references.pmid: 24743024
references.citation: Cancer Discov. 2014 Jul;4(7):816-27
references.pmid: 24771846
references.citation: Oncogene. 2015 Jun 4;34(23):2951-7
references.pmid: 25109330
references.citation: J Invest Dermatol. 2015 Feb;135(2):352-358
references.pmid: 25142731
references.citation: Cell Mol Life Sci. 2015 Apr;72(7):1249-60
references.pmid: 25433395
references.citation: Oncotarget. 2014 Nov 30;5(22):10969-75
references.pmid: 25473891
references.citation: Theranostics. 2015 Jan 01;5(3):302-21
references.pmid: 25553117
references.citation: Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):E420-9
references.pmid: 25605940
references.citation: J Invest Dermatol. 2015 Jul;135(7):1820-1828
references.pmid: 25705847
references.citation: J Invest Dermatol. 2015 Jul;135(7):1839-1848
references.pmid: 25751672
references.citation: Pigment Cell Melanoma Res. 2015 Jul;28(4):390-406
references.pmid: 25818589
references.citation: J Invest Dermatol. 2015 Aug;135(8):2040-2048
references.pmid: 25830652
references.citation: Lab Invest. 2015 Jun;95(6):672-83
references.pmid: 25867763
references.citation: Oncotarget. 2015 May 20;6(14):12297-309
references.pmid: 25909218
references.citation: Oncotarget. 2015 Aug 14;6(23):19552-79
references.pmid: 25980581
references.citation: PLoS One. 2015 Jun 02;10(6):e0128796
references.pmid: 26035829
references.citation: Nat Rev Cancer. 2015 Jul;15(7):397-408
references.pmid: 26105537
references.citation: J Invest Dermatol. 2015 Aug;135(8):1929-1933
references.pmid: 26174532
references.citation: Oncotarget. 2015 Sep 22;6(28):25452-65
references.pmid: 26327537
references.citation: Oncotarget. 2015 Oct 20;6(32):33554-67
references.pmid: 26378023
references.citation: Cell Mol Bioeng. 2015 Sep;8(3):455-470
references.pmid: 29552235