Noxa upregulation by oncogenic activation of MEK/ERK through CREB promotes autophagy in human melanoma cells
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Yi Lun Liu1,*, Fritz Lai1,*, James S. Wilmott2, Xu Guang Yan1, Xiao Ying Liu1, Qi Luan1, Su Tang Guo1,3, Chen Chen Jiang4, Hsin-Yi Tseng1, Richard A. Scolyer2, Lei Jin4 and Xu Dong Zhang1
1 School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia
2 Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
3 Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, China
4 School of Medicine and Public Health, The University of Newcastle, NSW, Australia
* These authors contributed equally to this work
Lei Jin , email:
Xu Dong Zhang, email:
Keywords: Noxa, Autophagy, MEK/ERK, CREB, Melanoma
Received: September 20, 2014 Accepted: October 21, 2014 Published: October 21, 2014
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.
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