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Ursolic and Oleanolic Acids Induce Mitophagy in A549 Human Lung Cancer Cells
Nayeli Shantal Castrejón-Jiménez1,2, Kahiry Leyva-Paredes3,4, Shantal Lizbeth Baltierra-Uribe5
1Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Ciudad de México 11340, Mexico. naye_nice85@hotmail.com.
Abstract:
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.
Insights
Ursolic and oleanolic acids induce autophagy and mitophagy in lung cancer cells, impacting cell viability. Blocking autophagy increases cell death, highlighting its role in cancer survival.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Ursolic and oleanolic acids are natural triterpenes with known anticancer properties.
- Autophagy, a cellular degradation process, plays a complex role in cancer progression and treatment response.
Purpose of the Study:
- To investigate the effects of ursolic and oleanolic acids on A549 human lung cancer cell viability.
- To elucidate the role of autophagy and mitophagy in mediating the activity of these triterpenes.
Main Methods:
- Confocal microscopy and western blotting were used to analyze autophagy induction, mitochondrial changes, and signaling pathways.
- Cell viability assays were performed following treatment with triterpenes and autophagy inhibitors (wortmannin).
Main Results:
- Both ursolic and oleanolic acids induced autophagy and mitophagy in A549 cells.
- Ursolic acid activated the AKT/mTOR pathway, while oleanolic acid acted independently of AKT.
- Triterpene treatment led to mitochondrial alterations, ROS production, and PINK1-dependent mitophagy.
- Inhibition of autophagy with wortmannin decreased mitochondrial membrane potential, increased p62/Nrf2, and caused cell death.
Conclusions:
- Mitophagy and the p62 protein are crucial survival mechanisms in A549 lung cancer cells.
- Targeting mitophagy and p62 may represent a therapeutic strategy for lung cancer treatment.
