Abstract
Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional treatments. Here we used a photoactive NADPH analogue called NS1 to induce cell death by inhibition of NADPH oxidases NOX in melanoma cells, including melanoma cells isolated from patients. In contrast, healthy melanocytes growth was unaffected by NS1 treatment.NS1 established an early Endoplasmic Reticulum stress by the early release of calcium mediated by (a) calcium-dependent redox-sensitive ion channel(s). These events initiated autophagy and apoptosis in all tested melanoma cells independently of their mutational status. The autophagy promoted by NS1 was incomplete. The autophagic flux was blocked at late stage events, consistent with the accumulation of p62, and a close localization of LC3 with NS1 associated with NS1 inhibition of NOX1 in autophagosomes. This hypothesis of a specific incomplete autophagy and apoptosis driven by NS1 was comforted by the use of siRNAs and pharmacological inhibitors blocking different processes. This study highlights the potential therapeutic interest of NS1 inducing cell death by triggering a selective ER stress and incomplete autophagy in melanoma cells harbouring wt and BRAF mutation.
Highlights
Cutaneous melanoma deriving from the transformation of melanocytes is one of the most lethal cancers among young adults
NS1 (30μM) strongly reduced the viability of multiple melanoma cells, SK-Mel28, which carried mutations of p53 and of BRAF, 1205 Lu cells mutated in BRAF and PTEN and melanoma cells freshly isolated from a patient at 72h without affecting the viability of healthy melanocytes (NHM) (Figure 1A)
This inhibition was obtained with DPI inhibiting flavoenzymes (30μM). 1205 Lu cells were more sensitive than other melanoma cell lines to Radical Oxygen Species (ROS) inhibition and DPI inhibited ROS levels to a larger extent than NS1 did
Summary
Cutaneous melanoma deriving from the transformation of melanocytes is one of the most lethal cancers among young adults. Encouraging results have recently been obtained with BRAF inhibitors, Vemurafenib (PLX4032) or Dabrafenib, and with MEK inhibitors [2] While these inhibitors [3,4,5] increase the lifetime expectancy of patients by about 6 months, regrettably, after a short period of remission, melanomas acquire drug resistance. Inhibition of ROS formed by NADPH oxidases (NOX) and/ or by eNOS uncoupling is highly requested for pharmacological treatments of oxidative stress associated with cancers [18]. NS1 inhibited melanoma cell growth [24] This process was dependent upon NS1 inducing a decrease of ROS formed in A375 cells.
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