title: Aurora B is regulated by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway and is a valuable potential target in melanoma cells.
abstract: Metastatic melanoma is a deadly skin cancer and is resistant to almost all existing treatment. Vemurafenib, which targets the BRAFV600E mutation, is one of the drugs that improves patient outcome, but the patients next develop secondary resistance and a return to cancer. Thus, new therapeutic strategies are needed to treat melanomas and to increase the duration of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor response. The ERK pathway controls cell proliferation, and Aurora B plays a pivotal role in cell division. Here, we confirm that Aurora B is highly expressed in metastatic melanoma cells and that Aurora B inhibition triggers both senescence-like phenotypes and cell death in melanoma cells. Furthermore, we show that the BRAF/ERK axis controls Aurora B expression at the transcriptional level, likely through the transcription factor FOXM1. Our results provide insight into the mechanism of Aurora B regulation and the first molecular basis of Aurora B regulation in melanoma cells. The inhibition of Aurora B expression that we observed in vemurafenib-sensitive melanoma cells was rescued in cells resistant to this drug. Consistently, these latter cells remain sensitive to the effect of the Aurora B inhibitor. Noteworthy, wild-type BRAF melanoma cells are also sensitive to Aurora B inhibition. Collectively, our findings, showing that Aurora B is a potential target in melanoma cells, particularly in those vemurafenib-resistant, may open new avenues to improve the treatment of metastatic melanoma.
authors: Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biologie et Pathologies des Mélanocytes de la Pigmentation Cutanée au Mélanome, Nice F-06204, France.
authors: Caroline
authors: C
authors: Bonet
authors: Sandy
authors: S
authors: Giuliano
authors: Mickaël
authors: M
authors: Ohanna
authors: Karine
authors: K
authors: Bille
authors: Maryline
authors: M
authors: Allegra
authors: Jean-Philippe
authors: JP
authors: Lacour
authors: Philippe
authors: P
authors: Bahadoran
authors: Stéphane
authors: S
authors: Rocchi
authors: Robert
authors: R
authors: Ballotti
authors: Corine
authors: C
authors: Bertolotto
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D051379:Mice; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; C482119:BRAF protein, human; C482120:Braf protein, mouse; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf