title: Apoptosis related protein-1 triggers melanoma cell death via interaction with the juxtamembrane region of p75 neurotrophin receptor.
abstract: Although chemotherapeutic drugs could theoretically target all metastatic sites, current treatments do not provide complementary therapeutics. Therefore, the development of an alternative approach replacing the traditional therapy is urgently needed. To assess the killing efficiency of the functionally identified apoptosis-related protein (APR)-1 in melanoma cells, we established a system for the regulated expression of APR-1. The induction of APR-1 expression caused apoptosis of melanoma cells via the interaction with the juxtamembrane region of p75 neurotrophin receptor (p75NTR), and possible also via the competition with tumour necrosis factor receptor-associated factor-6 (TRAF6) and the catalytic receptor of neurotrophin (Trk) for the same p75NTR interacting site. The accumulation of APR-1 in melanoma cells may block the physical association of p75NRT with TRAF6 and/or Trk, leading to the disruption of both NF-κB and extracellular signal-regulated kinase (ERK) pathways. Also, accumulation of APR-1 protein enhanced the activity of both c-Jun-N-terminal kinase (JNK) and p38 pathways. However, the analysis of APR-1-modulated pathways demonstrated the involvement of apoptosis-regulating kinase 1-JNK/p38 pathway in the induction of Bax expression leading to both mitochondrial dysregulation [as demonstrated by the loss of mitochondrial membrane potential, the release of both cytochrome c and apoptosis-inducing factor into cytoplasm, and cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP)] and endoplasmic reticulum stress as demonstrated by the increase of intracellular Ca(2+)  release. Thus, besides the analysis of its pro-apoptotic function, our data provide insight into the molecular mechanism of APR-1-induced apoptosis of melanoma cells.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM U977), University of Strasbourg, Strasbourg, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Selimovic
authors.forename: Achim
authors.initials: A
authors.lastname: Sprenger
authors.forename: Matthias
authors.initials: M
authors.lastname: Hannig
authors.forename: Youssef
authors.initials: Y
authors.lastname: Haïkel
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hassan
mesh_terms: D017209:Apoptosis; D002118:Calcium; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; D048029:TNF Receptor-Associated Factor 6; D051028:bcl-2-Associated X Protein; C076744:cytoplasmic linker protein 170; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; D002118:Calcium