Protein-Bound Polysaccharides from Coriolus Versicolor Induce RIPK1/RIPK3/MLKL-Mediated Necroptosis in ER-Positive Breast Cancer and Amelanotic Melanoma Cells

Pigmentation Levels Affect Melanoma Responses to Coriolus versicolor Extract and Play a Crucial Role in Melanoma-Mononuclear Cell Crosstalk

“…The data presented above clearly suggest that the pigmented phenotype of cells attenuates CV-induced toxicity and, conversely, that inhibition of melanogenesis by tyrosinase inhibitors sensitize melanoma cells to the anticancer action of this fungus extract. The results are consistent with the known properties of melanin being a ROS scavenger [ 12 , 24 ] and with our previous findings showing that CV-derived components induce ROS-mediated cell death only of non-pigmented melanoma cells [ 36 , 41 ]. Moreover, using the co-culture system of PBMCs with melanoma cells with different melanin content, we confirmed that melanogenesis has potent immunosuppressive properties.…”

“…Our previous data showed that CV bioactive components induce ROS- and JNK-dependent death of non-pigmented melanoma cells [ 36 ]. The observed cell death was independent of caspase and Bcl2 expression, and was mediated through induction of necroptosis, a form of programmed cell death [ 41 ]. To verify whether this pathway is also triggered by CV compounds in depigmented melanoma cells, we examined the potential involvement in this process of three kinases, including receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), which are the main executioners of necroptotic cell death.…”

“…Since we have shown that the accumulation of intracellular ROS is involved in the induction of necroptosis in non-pigmented melanoma cells [ 36 , 41 ], we examined the ROS generation in depigmented melanoma cells following CV stimulation. The cells were treated with CV extract (200 µg/mL) or incubated with PBS (as a control) for 24 h, and then stained with 2′,7′ dichlorofluorescin diacetate (DCFH-DA) to measure total intracellular ROS ( Figure 4 A,B).…”

“…Recently, using the SKMel-188 melanoma cell line, which represents a unique research model that allows for obtaining the results independent of individual cell line properties resulting from differences at the DNA level and thus enabling the conducting comparative studies on the biology of both forms of melanoma, we have demonstrated that CV fungus compounds cause Bcl-2- and caspase-independent cell death in non-pigmented melanoma cells [ 36 ]. Subsequent studies have revealed that CV induces the programmed form of necrosis [ 41 ]. This cytotoxic activity of CV extract was observed only in non-pigmented melanoma cells, while pigmented cells were resistant to the anticancer activity of this agent.…”

“…We showed that non-pigmented melanoma cell death induced by CV extract is dependent on ROS production, which is regulated by c-Jun N -terminal kinase (JNK) activity [ 36 ]. Then, we discovered that the inhibitors of RIPK1, RIPK3, and MLKL kinases diminished the intracellular ROS generation triggered by CV compounds in non-pigmented melanoma cells [ 41 ]. Knowing that ROS plays a role in regulating necroptosis in many cell types [ 65 ], we sought to determine whether a blockade of the melanogenesis pathway would also affect ROS generation in CV-stimulated melanoma cells.…”