title: Vinblastine-induced apoptosis of melanoma cells is mediated by Ras homologous A protein (Rho A) via mitochondrial and non-mitochondrial-dependent mechanisms.
abstract: Despite the availability of melanoma treatment at the primary site, the recurrence of local melanoma can metastasize to any distant organ. Currently, the available therapies for the treatment of metastatic melanoma are of limited benefit. Thus, the functional analysis of conventional therapies may help to improve their efficiency in the treatment of metastatic melanoma. In the present study, the exposure of melanoma cells to vinblastine was found to trigger apoptosis as evidenced by the loss of mitochondrial membrane potential, the release of both cytochrome c and apoptosis inducing factor, activation of caspase-9 and 3, and cleavage of Poly (ADP-ribose)-Polymerase. Also, vinblastine enhances the phosphorylation of Ras homologous protein A, the accumulation of reactive oxygen species, the release of intracellular Ca(2+), as well as the activation of apoptosis signal-regulating kinase 1, c-jun-N-terminal kinase, p38, inhibitor of kappaBα (IκBα) kinase, and inositol requiring enzyme 1α. In addition, vinblastine induces the DNA-binding activities of the transcription factor NF-κB, HSF1, AP-1, and ATF-2, together with the expression of HSP70 and Bax proteins. Moreover, inhibitory experiments addressed a central role for Rho A in the regulation of vinblastine-induced apoptosis of melanoma cells via mitochondrial and non-mitochondrial-dependent mechanisms. In conclusion, the present study addresses for the first time a central role for Rho A in the modulation of vinblastine-induced apoptosis of melanoma cells and thereby provides an insight into the molecular action of vinblastine in melanoma treatment.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 977, Faculty of Medicine and Dental Faculty, 11 Rue Humann, 67000 Strasbourg, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Selimovic
authors.forename: Helene E
authors.initials: HE
authors.lastname: Badura
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: El-Khattouti
authors.forename: Martine
authors.initials: M
authors.lastname: Soell
authors.forename: Benjamin B O W
authors.initials: BB
authors.lastname: Porzig
authors.forename: Achim
authors.initials: A
authors.lastname: Spernger
authors.forename: Foued
authors.initials: F
authors.lastname: Ghanjati
authors.forename: Simeon
authors.initials: S
authors.lastname: Santourlidis
authors.forename: Youssef
authors.initials: Y
authors.lastname: Haikel
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hassan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D014747:Vinblastine; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020742:rhoA GTP-Binding Protein; D002118:Calcium