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Cell Death Dis. 2019 Nov 28;10(12):902. doi: 10.1038/s41419-019-2143-7.

Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis.

Author information

1
Department of Biology, University of Rome Tor Vergata, Rome, Italy.
2
Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
3
Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy.
4
Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy.
5
Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
6
Laboratory of Molecular Medicine, Institute of Cytology of the Russian Academy of Sciences, Saint Petersburg, Russia.
7
Laboratory of Intracellular Signaling, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russian Federation.
8
Department of Biology, University of Rome Tor Vergata, Rome, Italy. mauro.piacentini@uniroma2.it.
9
Laboratory of Molecular Medicine, Institute of Cytology of the Russian Academy of Sciences, Saint Petersburg, Russia. mauro.piacentini@uniroma2.it.
10
Department of Health Sciences, University of Piemonte Orientale, Novara, Italy. marco.corazzari@med.uniupo.it.
11
Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy. marco.corazzari@med.uniupo.it.
12
Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy. marco.corazzari@med.uniupo.it.

Abstract

The incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side effects such as autoimmune disorders could limit its clinical use. Alternative therapeutic strategies are therefore urgently needed to efficiently kill melanoma cells. Ferroptosis induction and execution were evaluated in metastasis-derived wild-type and oncogenic BRAF melanoma cells, and the process responsible for the resistance has been dissected at molecular level. Although efficiently induced in all cells, in an oncogenic BRAF- and ER stress-independent way, most cells were resistant to ferroptosis execution. At molecular level we found that: resistant cells efficiently activate NRF2 which in turn upregulates the early ferroptotic marker CHAC1, in an ER stress-independent manner, and the aldo-keto reductases AKR1C1 ÷ 3 which degrades the 12/15-LOX-generated lipid peroxides thus resulting in ferroptotic cell death resistance. However, inhibiting AKRs activity/expression completely resensitizes resistant melanoma cells to ferroptosis execution. Finally, we found that the ferroptotic susceptibility associated with the differentiation of melanoma cells cannot be applied to metastatic-derived cells, due to the EMT-associated gene expression reprogramming process. However, we identified SCL7A11 as a valuable marker to predict the susceptibility of metastatic melanoma cells to ferroptosis. Our results identify the use of pro-ferroptotic drugs coupled to AKRs inhibitors as a new valuable strategy to efficiently kill human skin melanoma cells.

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