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

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 (IC 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.

The Roles of Autophagy in Cancer

“…RAS-activating mutation increases autophagy, which enhances tumor growth, survival, and oncogenesis, and is associated with the development of some deadly cancers, including lung, colon, and pancreatic [ 82 , 83 , 84 , 85 ]. Some studies have revealed that a high level of autophagy is observed in RAS-activating mutated cells, and cell survival is dependent on autophagy during nutrient starvation [ 86 , 87 ]. In addition, inhibition of autophagy-related protein enhances the accumulation of damaged mitochondria and decreases cell growth [ 88 , 89 , 90 ].…”

A Droplet Microfluidics Based Platform for Mining Metagenomic Libraries for Natural Compounds

“…The production of violacein evolved as a defense for C. violaceum biofilms and phagocytosis of a single C. violaceum results in lysis, release of violacein, and induction of apoptosis in protozoa [ 45 ]. Additionally, violacein has been shown to be toxic not only to protozoa but also to induce apoptosis in a range of human cancer cell lines [ 46 , 47 , 48 , 49 , 50 ]. Furthermore, violacein is insoluble in water [ 51 ] and thus fits our model of identifying natural compounds that may or may not require specific solvents for mammalian cell assays.…”

Sepsis caused by Chromobacterium violaceum – probably the first case in Europe, or <i>Macbeth</i> read anew

“…On a more optimistic note, it is worth mentioning the attempts to use violacein to treat gastroenterological diseases, including malignancies, and well as other cancers, e.g. melanoma [12,13,14].…”