Mechanism of melanoma cells selective apoptosis induced by a photoactive NADPH analogue

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.

E2F1 inhibition mediates cell death of metastatic melanoma

“…Cells were stained with DAPI and Annexin V or Cell ROX Deep Red and analyzed using fluorescence-activated cell sorter (MACSQuant Analyzer) and MACSQuantify software as described 32 .…”

3′RR targeting in lymphomagenesis: a promising strategy?

“…In conclusion, the 3 0 RR is considered as a major lymphoma oncogene deregulator, [3][4][5] and its deletion has no effect on immune and inflammatory responses in the pristane mouse model. It is, thus, tempting to speculate that the 3 0 RR might be considered as a potential suitable target for anti-lymphoma pharmacological therapy without significant impact on the normal immune and inflammatory networks.…”

“…4 Interestingly the phenotype of lymphoproliferations induced by the c-myc-3 0 RR transgene is affected by the presence of associated mutations in key cell cycle dependent genes such as p53 or Cdk4. 5 Knock-out models have clarified the functions of the 3 0 RR as essential for high-rate IgH transcription at the plasma cell stage. 2 3 0 RR may thus be a potent activator of IgH-translocated oncogene transcription, even when the breakpoints lie several hundred kb away from the 3 0 RR.…”

A new 3′RR regulatory role during lymphomagenesis

“…Indeed, B-cells bearing the same initial oncogenic events can lead to different B-cell lymphoma subtypes if their development is impaired, while different mutations occurring in the same cell of origin can induce similar tumors. 4 In this context, we also show that the 3 0 RR can affect the phenotype of B-cell lymphomas due to oncogene translocation in other loci than the IgH one, by acting on B-cell maturation and regulating potentially oncogenic recombination and mutations during late B-cell differentiation. …”

“…3 Chromosomal translocations linking oncogenes to these elements are implicated in various B-cell malignancies. [3][4][5] If the deregulation of the translocated oncogene by enhancer elements located in cis was extensively studied, 4,5 little is known about a potential trans effect of the Ig enhancers, for example the role of the IgH 3 0 RR on lymphomagenesis caused by an oncogene translocation to the IgL locus. Indeed, studies have shown that deletion of the 3 0 RR modulates the B-cell fate by lowering the BCR signaling, 6 which is of key importance in B-cell malignancies.…”