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Open AccessArticle

Ursolic and Oleanolic Acids Induce Mitophagy in A549 Human Lung Cancer Cells

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Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Ciudad de México 11340, Mexico
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Área Académica de Medicina Veterinaria y Zootecnia, Instituto de Ciencias Agropecuarias-Universidad Autónoma del Estado de Hidalgo, Av. Universidad km. 1. Exhacienda de Aquetzalpa A.P. 32, Tulancingo 43600, Hidalgo, Mexico
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Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Ciudad de México 11340, Mexico
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Laboratorio de Inmunología Integrativa, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Calz. de Tlalpan 4502, Belisario Domínguez Secc. 16, Ciudad de México 14080, Mexico
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Departamento de Anatomía Patológica, Instituto Nacional de Rehabilitación, México-Xochimilco No. 289. Arenal de Guadalupe, Ciudad de México 14389, Mexico
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Departamento de Neurociencias, Instituto Nacional de Rehabilitación, México-Xochimilco No. 289, Arenal de Guadalupe, Ciudad de México 14389, Mexico
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Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Ciudad de México 11340, Mexico
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Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Salvador Díaz Mirón esq. Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo Tomas, Ciudad de México 11340, Mexico
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Subdirección de Enseñanza e Investigación, División de Investigación Biomédica, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Félix Cuevas 540, Col del Valle Sur, Ciudad de México 03100, Mexico
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Sección de Estudios de Posgrado e Investigación, Escuela Superior de Ingeniería Mecánica y Eléctrica Unidad Zacatenco, Instituto Politécnico Nacional, Gustavo A. Madero, Ciudad de México 07738, Mexico
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2019, 24(19), 3444; https://doi.org/10.3390/molecules24193444
Received: 17 August 2019 / Revised: 3 September 2019 / Accepted: 7 September 2019 / Published: 23 September 2019
(This article belongs to the Section Natural Products Chemistry)
Ursolic and oleanolic acids are natural isomeric triterpenes known for their anticancer activity. Here, we investigated the effect of triterpenes on the viability of A549 human lung cancer cells and the role of autophagy in their activity. The induction of autophagy, the mitochondrial changes and signaling pathway stimulated by triterpenes were systematically explored by confocal microscopy and western blotting. Ursolic and oleanolic acids induce autophagy in A549 cells. Ursolic acid activates AKT/mTOR pathways and oleanolic acid triggers a pathway independent on AKT. Both acids promote many mitochondrial changes, suggesting that mitochondria are targets of autophagy in a process known as mitophagy. The PINK1/Parkin axis is a pathway usually associated with mitophagy, however, the mitophagy induced by ursolic or oleanolic acid is just dependent on PINK1. Moreover, both acids induce an ROS production. The blockage of autophagy with wortmannin is responsible for a decrease of mitochondrial membrane potential (Δψ) and cell death. The wortmannin treatment causes an over-increase of p62 and Nrf2 proteins promote a detoxifying effect to rescue cells from the death conducted by ROS. In conclusion, the mitophagy and p62 protein play an important function as a survival mechanism in A549 cells and could be target to therapeutic control. View Full-Text
Keywords: ursolic acid; oleanolic acid; mitophagy; A549 human lung cancer cells; reactive oxygen species; PINK1/Parkin ursolic acid; oleanolic acid; mitophagy; A549 human lung cancer cells; reactive oxygen species; PINK1/Parkin
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MDPI and ACS Style

Castrejón-Jiménez, N.S.; Leyva-Paredes, K.; Baltierra-Uribe, S.L.; Castillo-Cruz, J.; Campillo-Navarro, M.; Hernández-Pérez, A.D.; Luna-Angulo, A.B.; Chacón-Salinas, R.; Coral-Vázquez, R.M.; Estrada-García, I.; Sánchez-Torres, L.E.; Torres-Torres, C.; García-Pérez, B.E. Ursolic and Oleanolic Acids Induce Mitophagy in A549 Human Lung Cancer Cells. Molecules 2019, 24, 3444.

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