Abstract
Heme oxygenase 1 (HO-1) plays a key role in maintaining cell redox balance. Under stress conditions, HO-1 is up-regulated and generates bilirubin, ferritin and carbon monoxide, with antioxidant, antiapoptotic and anti-inflammatory properties [Jozkowicz et al., 2007]. HO-1 induction favors cancer progression [Furfaro et al., 2016] and its involvement in tumor resistance to therapy [Was et al., 2006] and immune-escape has been highlighted in melanoma-bearing mice [Di Biase et al., 2016]. In this work, the role of HO-1 in melanoma cell resistance to Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600 has been investigated, as well as HO-1 involvement in natural killer (NK)-mediated killing. BRAFV600E mutant primary melanoma cells isolated in our lab have been treated for 24 h with 1 μM PLX4032. The treatment reduced viability (-23%), increased HO-1 mRNA level of two-fold, and decreased the ability of IL-15 activated NK cells to degranulate in response to PLX4032-treated cells, when compared to untreated melanoma cells. HO-1 silencing increased PLX4032 efficacy further reducing cell viability to 47% in comparison to cells treated with PLX4032 alone and restored the degranulation potential of NK. Thus, we hypothesize that HO-1 inhibition can effectively improve the efficacy of mutant-BRAF inhibitors and favors NK-depending killing of PLX4032-treated melanoma cells.
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