Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations
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Mariusz L. Hartman1, Beata Talar1, Malgorzata Sztiller-Sikorska1, Dariusz Nejc2, Malgorzata Czyz1
1Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland
2Department of Surgical Oncology, Medical University of Lodz, Lodz, Poland
Malgorzata Czyz, e-mail: firstname.lastname@example.org
Keywords: melanoma, MITF, NF-κB, parthenolide, cellular senescence
Received: September 30, 2015 Accepted: January 20, 2016 Published: January 27, 2016
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.
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