Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy

Abstract

Ursolic acid (UA) has been reported to possess anticancer activities. Although some of the anticancer activities of UA have been explained by its apoptosis-inducing properties, the mechanisms underlying its anticancer actions are largely unknown. We have found that UA-activated autophagy induced cytotoxicity and reduced tumor growth of cervical cancer cells TC-1 in a concentration-dependent manner. UA did not induce apoptosis of TC-1 cells in vitro as determined by annexin V/propidium iodide staining, DNA fragmentation, and Western blot analysis of the apoptosis-related proteins. We found that UA increased punctate staining of light chain 3 (LC3), which is an autophagy marker. LC3II, the processed form of LC3I which is formed during the formation of double membranes, was induced by UA treatment. These results were further confirmed by transmission electron microscopy. Wortmannin, an inhibitor of autophagy, and a small interfering RNA (siRNA) for autophagy-related genes (Atg5) reduced LC3II and simultaneously increased the survival of TC-1 cells treated with UA. We also found that LC3II was significantly reduced and that survival was increased in Atg52/2 mouse embryonic fibroblast (MEF) cells compared to Atg51/1 MEF cells under UA treatment. However, silencing BECN1 by siRNA affected neither the expression of LC3II nor the survival of TC-1 cells under UA treatment. These results suggest that autophagy is a major mechanism by which UA kills TC-1 cells. It is Atg5 rather than BECN1 that plays a crucial role in UA-induced autophagic cell death in TC-1 cells. The activation of autophagy by UA may become a potential cancer therapeutic strategy complementing the apoptosis-based therapies. Furthermore, regulation of Atg5 may improve the efficacy of UA in cancer treatment.

The combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway

“…It has been used for pharmaceutical, cosmetic and food preparations. Of note, ursolic acid has garnered much attention as a therapeutic compound in a number of diseases, such as cancer (9), diabetes (10), Alzheimer's disease (11) and obesity (12), due to its anti-inflamThe combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway matory and antitumor properties. Moreover, this triterpene has been reported to increase the insulin-induced phosphorylation of Akt, a serine/threonine-specific protein kinase, that plays a key role in multiple cellular processes, such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration (13).…”

Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation

“…UA is pentacyclic triterpenoid that is ubiquitously expressed in most plant species [8] . UA has been shown to exert anti-cancer [9] , anti-oxidative [10] , and anti-inflammatory [11] effects, in addition to conferring benefits in cognitive function [12] , asthma [13] , and colon cancer [14,15] . Of note, Pathak et al reported that UA inhibited activation of the STAT3 pathway, leading to the suppression of proliferation in human multiple myeloma cells [16] .…”

Cytotoxic Triterpenes and Sterols from Pipturus arborescens (Link) C.B. Rob.

“…A recent study reported that 3a inhibited cell growth and proliferation of Jurkat leukemic T-cells, inhibiting PMA/PHA induced IL-2 and TNF-α production in a concentration and time dependent manner (Kaewthawee and Brimson, 2013). A study on cervical cancer cells TC-1 reported that ursolic acid-activated autophagy induced cytotoxicity and reduced tumor growth in a concentration-dependent manner Leng et al, 2013). Another study evaluated the antitumor activities of 3a on U87MG brain cancer cells and found that both G1-phase arrest and autophagy were induced by the compound (Shen et al, 2014).…”