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.
Highlights
Ursolic and oleanolic acids are ubiquitous compounds widely distributed in plants and fruits as a result of a fascinating secondary metabolism
Our results show that after mitochondrial net fragmentation, the expression of PINK1 was increased in A549 cells treated with ursolic or oleanolic acid, but, just the oleanolic acid slightly increases the Parkin protein level, indicating that the mitophagy process observed was independent on the activation of Parkin
The PINK1/Parkin pathway has been reported as a mediator of mitophagy in A549 cells stimulated by paraquat [34] and several isoforms of Parkin have been detected in A549 cell [35], our results suggest that ursolic or oleanolic acids induce a mitophagy process independent on Parkin in epithelial cells
Summary
Ursolic and oleanolic acids are ubiquitous compounds widely distributed in plants and fruits as a result of a fascinating secondary metabolism. The compounds produced by their typical primary metabolism are necessary for growth and development, while the compounds emerging from secondary metabolism have other functions that are still being elucidated. Both acids are synthetized from isoprene and have 30 carbon atoms organized in five pentacyclic rings; based on this characteristic structure, both acids are classified as triterpenes [1]. Ursolic acid has been evaluated against different models of cancer, cervical [3], prostate [4,5], and lung [6]; among others. The variances in biological activity might be due to structural differences, mainly a methyl group in the E ring of oleanolic acid [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
