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Regulation of viability, differentiation and death of human melanoma cells carrying neural stem cell biomarkers: a possibility for neural trans-differentiation

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Abstract

During embryonic development, melanoblasts, the precursors of melanocytes, emerge from a subpopulation of the neural crest stem cells and migrate to colonize skin. Melanomas arise during melanoblast differentiation into melanocytes and from young proliferating melanocytes through somatic mutagenesis and epigenetic regulations. In the present study, we used several human melanoma cell lines from the sequential phases of melanoma development (radial growth phase, vertical growth phase and metastatic phase) to compare: (i) the frequency and efficiency of the induction of cell death via apoptosis and necroptosis; (ii) the presence of neural and cancer stem cell biomarkers as well as death receptors, DR5 and FAS, in both adherent and spheroid cultures of melanoma cells; (iii) anti-apoptotic effects of the endogenous production of cytokines and (iv) the ability of melanoma cells to perform neural trans-differentiation. We demonstrated that programed necrosis or necroptosis, could be induced in two metastatic melanoma lines, FEMX and OM431, while the mitochondrial pathway of apoptosis was prevalent in a vast majority of melanoma lines. All melanoma lines used in the current study expressed substantial levels of pluripotency markers, SOX2 and NANOG. There was a trend for increasing expression of Nestin, an early neuroprogenitor marker, during melanoma progression. Most of the melanoma lines, including WM35, FEMX and A375, can grow as a spheroid culture in serum-free media with supplements. It was possible to induce neural trans-differentiation of 1205Lu and OM431 melanoma cells in serum-free media supplemented with insulin. This was confirmed by the expression of neuronal markers, doublecortin and β3-Tubulin, by significant growth of neurites and by the negative regulation of this process by a dominant-negative Rac1N17. These results suggest a relative plasticity of differentiated melanoma cells and a possibility for their neural trans-differentiation without the necessity for preliminary dedifferentiation.

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Abbreviations

EGF:

Epidermal growth factor

ERK1/2:

Extracellular-signal-regulated kinases

FACS:

Fluorescence-activated cell sorter

FGF2:

Fibroblast growth factor-2 (basic)

IκB:

Inhibitor of NF-κB

IKK:

Inhibitor nuclear factor kappa B kinase

JNK:

C-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MEK:

MAPK/ERK kinase

NF-κB:

Nuclear factor kappa B

NSC:

Neural stem cells

PARP-1:

Poly (ADP-ribose) polymerase-1

PI:

Propidium iodide

PI3K:

Phosphoinositide 3-kinase

STAT:

Signal transducers and activators of transcription

TNFα:

Tumor necrosis factor

zVAD:

Carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone

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Acknowledgments

We would like to thank Drs. Peter Grabham and Howard Lieberman for advice, critical reading of the manuscript and discussion. This work was supported by Pilot Grant of the Department of Dermatology, Columbia University (P30AR044531-11, Project GG006336) and NIH Grant 5R01-ES12888-07.

Conflict of interest

The authors declare that there are no conflicts of interest.

Compliance with Ethical Standards

Animals were not used in this research. Participation of human subjects did not occur in this study.

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  1. Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA

    Vladimir N. Ivanov & Tom K. Hei

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  1. Vladimir N. Ivanov
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Correspondence to Vladimir N. Ivanov.

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Ivanov, V.N., Hei, T.K. Regulation of viability, differentiation and death of human melanoma cells carrying neural stem cell biomarkers: a possibility for neural trans-differentiation. Apoptosis 20, 996–1015 (2015). https://doi.org/10.1007/s10495-015-1131-3

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  • DOI: https://doi.org/10.1007/s10495-015-1131-3

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