title: Imiquimod-induced apoptosis of melanoma cells is mediated by ER stress-dependent Noxa induction and enhanced by NF-κB inhibition.
abstract: Melanoma is characterized by dysregulated intracellular signalling pathways including an impairment of the cell death machinery, ultimately resulting in melanoma resistance, survival and progression. This explains the tumour's extraordinary resistance to the standard treatment. Imiquimod is a topical immune response modifier (imidazoquinoline) with both antiviral and antitumour activities. The mechanism by which imiquimod triggers the apoptosis of melanoma cells has now been carefully elucidated. Imiquimod-induced apoptosis is associated with the activation of apoptosis signalling regulating kinase1/c-Jun-N-terminal kinase/p38 pathways and the induction of endoplasmic stress characterized by the activation of the protein kinase RNA-like endoplasmic reticulum kinase signalling pathway, increase in intracellular Ca(2+) release, degradation of calpain and subsequent cleavage of caspase-4. Moreover, imiquimod triggers the activation of NF-κB and the expression of the inhibitor of apoptosis proteins (IAPs) such as, X-linked IAP (XIAP) together with the accumulation of reactive oxygen species (ROS). Also, imiquimod triggers mitochondrial dysregulation characterized by the loss of mitochondrial membrane potential (Δψm), the increase in cytochrome c release, and cleavage of caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP). Inhibitors of specific pathways, permit the elucidation of possible mechanisms of imiquimod-induced apoptosis. They demonstrate that inhibition of NF-kB by the inhibitor of nuclear factor kappa-B kinase (IKK) inhibitor Bay 11-782 or knockdown of XIAP induces melanoma apoptosis in cells exposed to imiquimod. These findings support the use of either IKK inhibitors or IAP antagonists as adjuvant therapies to improve the effectiveness topical imiquimod in the treatment of melanoma.
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: El-Khattouti
authors.affiliation: Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, University Hospital of Saarland, Homburg/Saar, Germany.
authors.forename: Denis
authors.initials: D
authors.lastname: Selimovic
authors.affiliation: Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, University Hospital of Saarland, Homburg/Saar, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hannig
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Taylor
authors.affiliation: Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.affiliation: Clinic of Dermatology, University Hospital of Aachen, Aachen, Germany.
authors.forename: Sofie Y
authors.initials: SY
authors.lastname: Hassan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, Strasbourg, France.|Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, Strasbourg, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Haikel
authors.affiliation: Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Emad
authors.initials: E
authors.lastname: Kandil
authors.affiliation: Clinic of Dermatology, University Hospital of Aachen, Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Leverkus
authors.affiliation: Department of Dermatology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Brodell
authors.affiliation: Clinic of Dermatology, University Hospital of Aachen, Aachen, Germany.
authors.forename: Mosaad
authors.initials: M
authors.lastname: Megahed
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.|Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, University Hospital of Saarland, Homburg/Saar, Germany.|Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, Strasbourg, France.|Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D000077271:Imiquimod; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D016328:NF-kappa B; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051636:X-Linked Inhibitor of Apoptosis Protein; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; D000077271:Imiquimod; D002118:Calcium
keywords: ER stress; NF-κB; apoptosis; imiquimod; melanoma