Publication: Suppression of antifolate resistance by targeting the myosin va trafficking pathway in melanoma
Authors
Fernández Pérez, Maria Piedad ; Sáez Ayala, Magalí ; Piñero Madrona, Antonio ; Cabezas Herrera, Juan ; Montenegro Arce, María Fernanda ; Rodríguez López, José Neptuno ; Sánchez del Campo Ferrer, Luis
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Publisher
Elsevier
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DOI
https://doi.org/10.1593/neo.13320
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info:eu-repo/semantics/article
Description
© 2013 Neoplasia Press, Inc. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
This document is the Published version of a Published Work that appeared in final form in Neoplasia. To access the final edited and published work see https://doi.org/10.1593/neo.13320
Abstract
Human melanoma is a significant clinical problem. As most melanoma patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is one of the highest priorities to improve melanoma therapy. Melanosomal sequestration and the cellular exportation of cytotoxic drugs have been proposed to be important melanoma-specific mechanisms that contribute to multidrug resistance in melanoma. Concretely, we found that treatment of melanoma with methotrexate (MTX) altered melanogenesis and accelerated the exportation of melanosomes; however, the cellular and molecular processes by which MTX is trapped into melanosomes and exported out of cells have not been elucidated. In this study, we identified myosin Va (MyoVa) as a possible mediator of these cellular processes. The results demonstrated that melanoma treatment with MTX leads to Akt2-dependent MyoVa phosphorylation, which enhances its ability to interact with melanosomes and accelerates their exportation. To understand the mechanism(s) by which MTX activates Akt2, we examined the effects of this drug on the activity of protein phosphatase 2A, an Akt inhibitor activated by the methylation of its catalytic subunit. Taken together, this study identified a novel trafficking pathway in melanoma that promotes tumor resistance through Akt2/MyoVa activation. Because of these findings, we explored several MTX combination therapies to increase the susceptibility of melanoma to this drug. By avoiding MTX exportation, we observed that the E2F1 apoptotic pathway is functional in melanoma, and its induction activates p73 and apoptosis protease-activating factor 1 following a p53-autonomous proapoptotic signaling event.
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Citation
Neoplasia, 2013, Vol. 15, N. 7, pp. 826–839
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Este ítem está sujeto a una licencia Creative Commons. http://creativecommons.org/licenses/by-nc-nd/4.0/