title: Noxa upregulation by oncogenic activation of MEK/ERK through CREB promotes autophagy in human melanoma cells.
abstract: Reduction in the expression of the anti-survival BH3-only proteins PUMA and Bim is associated with the pathogenesis of melanoma. However, we have found that the expression of the other BH3-only protein Noxa is commonly upregulated in melanoma cells, and that this is driven by oncogenic activation of MEK/ERK. Immunohistochemistry studies showed that Noxa was expressed at higher levels in melanomas than nevi. Moreover, the expression of Noxa was increased in metastatic compared to primary melanomas, and in thick primaries compared to thin primaries. Inhibition of oncogenic BRAFV600E or MEK downregulated Noxa, whereas activation of MEK/ERK caused its upregulation. In addition, introduction of BRAFV600E increased Noxa expression in melanocytes. Upregulation of Noxa was due to a transcriptional increase mediated by cAMP responsive element binding protein, activation of which was also increased by MEK/ERK signaling in melanoma cells. Significantly, Noxa appeared necessary for constitutive activation of autophagy, albeit at low levels, by MEK/ERK in melanoma cells. Furthermore, it was required for autophagy activation that delayed apoptosis in melanoma cells undergoing nutrient deprivation. These results reveal that oncogenic activation of MEK/ERK drives Noxa expression to promote autophagy, and suggest that Noxa has an indirect anti-apoptosis role in melanoma cells under nutrient starvation conditions.
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Yi Lun
authors.initials: YL
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia. Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Fritz
authors.initials: F
authors.lastname: Lai
authors.affiliation: Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Xu Guang
authors.initials: XG
authors.lastname: Yan
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Xiao Ying
authors.initials: XY
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Luan
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia. Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, China.
authors.forename: Su Tang
authors.initials: ST
authors.lastname: Guo
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW, Australia.
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Tseng
authors.affiliation: Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW, Australia.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
mesh_terms: D001343:Autophagy / Q000502:physiology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases