Tumor Biology

, Volume 37, Issue 10, pp 14049–14058 | Cite as

Violacein induces death of RAS-mutated metastatic melanoma by impairing autophagy process

  • Paola R. Gonçalves
  • Karin J. P. Rocha-Brito
  • Maruska R. N. Fernandes
  • Julia L. Abrantes
  • Nelson Durán
  • Carmen V. Ferreira-Halder
Original Article

Abstract

Treatment of metastatic melanoma still remains a challenge, since in advanced stage it is refractory to conventional treatments. Most patients with melanoma have either B-RAF or N-RAS mutations, and these oncogenes lead to activation of the RAS-RAF-MEK-ERK and AKT signal pathway, keeping active the proliferation and survival pathways in the cell. Therefore, the identification of small molecules that block metastatic cell proliferation and induce cell death is needed. Violacein, a pigment produced by Chromobacterium violaceum found in Amazon River, has been used by our group as a biotool for scrutinizing signaling pathways associated with proliferation, survival, aggressiveness, and resistance of cancer cells. In the present study, we demonstrate that violacein diminished the viability of RAS- and RAF-mutated melanoma cells (IC50 value ∼500 nM), and more important, this effect was not abolished after treatment medium removal. Furthermore, violacein was able to reduce significantly the invasion capacity of metastatic melanoma cells in 3D culture. In the molecular context, we have shown for the first time that violacein causes a strong drop on histone deacetylase 6 expression, a proliferating activator, in melanoma cells. Besides, an inhibition of AXL and AKT was detected. All these molecular events propitiate an inhibition of autophagy, and consequently, melanoma cell death by apoptosis.

Keywords

Violacein Antitumor activity Melanoma Skin carcinoma Autophagy 

Abbreviations

B-RAF

B-RAF proto-oncogene, serine/threonine kinase

N-RAS

N-RAS proto-oncogene, member of the RAS gene family

MEK

Mitogen-activated protein kinase kinase

ERK

Extracellular signal-regulated kinase

AKT

Serine/threonine-specific protein kinase

AXL

Tyrosine-protein kinase receptor UFO

LC3-I/II

Microtubule-associated proteins 1A/1B light chains 3A/LC3A and 3B/LC3B

p62

Sequestosome-1

p21

Cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1

PARP-1

Poly(ADP-ribose) polymerase-1

mTOR

Mammalian target of rapamycin, Ser/Thr protein kinase

HSP90

Heat shock protein 90 kDa

HDAC

Histone deacetylase

SIRT

NAD-dependent deacetylase sirtuin-1

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Paola R. Gonçalves
    • 1
    • 2
  • Karin J. P. Rocha-Brito
    • 2
  • Maruska R. N. Fernandes
    • 2
  • Julia L. Abrantes
    • 2
  • Nelson Durán
    • 3
    • 4
  • Carmen V. Ferreira-Halder
    • 2
    • 5
  1. 1.Departamento de Ciências da Saúde, Centro Universitário Norte do Espírito SantoUniversidade Federal do Espírito SantoSão MateusBrazil
  2. 2.Departamento de Bioquímica e Biologia Tecidual, Instituto de BiologiaUniversidade Estadual de CampinasCampinasBrazil
  3. 3.Institute of ChemistryUniversidade Estadual de CampinasCampinasBrazil
  4. 4.Brazilian Nanotechnology National Laboratory (LNNano-CNPEM)CampinasBrazil
  5. 5.Unicamp. Rua Monteiro LobatoCidade Universitária ZeferinoCampinasBrazil

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