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      Adaptive redox homeostasis in cutaneous melanoma

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          Abstract

          Cutaneous melanoma is the most aggressive type of skin cancer. Although cutaneous melanoma accounts for a minority of all types of skin cancer, it causes the greatest number of skin cancer related deaths worldwide. Oxidative stress and redox homeostasis have been shown to be involved at each stage of a malignant melanocyte transformation, called melanomagenesis, as well as during drug resistance. Reactive oxygen species (ROS) play an important and diverse role that regulate many aspects of skin cell behaviors ranging from proliferation and stemness, to oxidative damage and cell death. On the other hand, antioxidants are associated with melanoma spread and metastasis. Overall, the contribution of redox homeostasis to melanoma development and progression is controversial and highly complex. The aim of this study is to examine the association between redox homeostasis and the melanomagenic process. To this purpose we are presenting what is currently known about the role of ROS in melanoma initiation and progression. In addition, we are discussing the role of antioxidant mechanisms during the spread of the disease and in cases of melanoma drug resistance. Although challenging, targeting redox homeostasis in melanoma progression remains to be a promising therapeutic approach, especially valid during melanoma drug resistance.

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          Most cited references102

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          Modulation of oxidative stress as an anticancer strategy.

          The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.
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            Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis.

            Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
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              Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

              Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer 1 . Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 and its repressor protein Keap1 2-5 . In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, suggesting that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic 6 . Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of K-Ras, B-Raf and Myc, and find that ROS are actively suppressed by these oncogenes. K-RasG12D, B-RafV619E and MycERT2 each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a novel mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-RasG12D and B-RafV619E, and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-RasG12D-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                08 October 2020
                October 2020
                08 October 2020
                : 37
                : 101753
                Affiliations
                [a ]Department of Biology, University of Padua, 35131, Italy
                [b ]Veneto Institute of Molecular Medicine (VIMM), Via Orus 2, 35129, Padua, Italy
                Author notes
                []Corresponding author. Department of Biology, University of Padua, 35131, Italy. massimo.santoro@ 123456unipd.it
                Article
                S2213-2317(20)30958-7 101753
                10.1016/j.redox.2020.101753
                7578258
                33091721
                7e53be14-2473-4ddc-a267-bdc1b7a752a1
                © 2020 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 July 2020
                : 16 September 2020
                : 5 October 2020
                Categories
                Review Article

                cutaneous melanoma,melanomagenesis,ros,redox homeostasis,metastasis,tumor metabolism,brafi-resistant melanoma,antioxidants

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