Ursolic Acid Induces Apoptosis Through Mitochondrial Intrinsic Pathway and Suppression of ERK1/2 MAPK in HeLa Cells

Abstract

Abstract. Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has been demonstrated to induce apoptosis in various tumors. The aim of the present study was to elucidate the molecular mechanisms of UA-induced apoptosis in HeLa cells. Here, we reported that UA induced apoptosis through the mitochondrial intrinsic pathway in HeLa cells, as shown by release of cytosol cytochrome c, activation of caspase-9 and -3, reduction of Bcl-2 and Bcl-xL, and increase of Bax and Bak. UA down-regulated the phosphorylation of ERK1/2 and p38, whereas phosphorylation of JNK was unchanged. The roles of ERK1/2 and p38 were further confirmed using the ERK1/2 inhibitor (U0126) and p38 inhibitor (SB203580). U0126 markedly increased UA-induced the Bax/Bcl-2 ratio, the increase of cytosol cytochrome c, and the levels of cleaved caspase-3, but SB203580 had little effects on the above characters, suggesting the ERK1/2 signaling pathway is required for apoptosis. Furthermore, UA up-regulated DUSP 1, 2, 4, 5, 6, 7, 9, and 10 mRNA expressions, which may be a clue for the role of dephosphorylation of ERK1/2 and p38. These data suggested that the apoptotic mechanism of UA treatment in HeLa cells was through the mitochondrial intrinsic pathway and closely associated with the suppression of the ERK1/2 signaling pathway.

Thymoquinone, a bioactive component of Nigella sativa Linn seeds or traditional spice, attenuates acute hepatic failure and blocks apoptosis via the MAPK signaling pathway in mice

“…27,28 Bcl-2 and Bax are essential for apoptosis and in the eventual activation of caspase in Bcl-2 family. 31 In this study, we showed that administration of TQ markedly decreased the Bax/Bcl-2 ratio induced by D-GalN/LPS (Fig. 30 Regardless of how the JNK signaling regulates the Bcl-2 superfamily members, as a whole, Bax/Bcl-2 ratio determine whether the cell survives or apoptosis.…”

Therapeutic effect of ursolic acid in experimental visceral leishmaniasis

“…In this regard, UA seems to be an interesting target to develop new formulations to be used in human health, because different reports demonstrated its multivalent activities against pathological conditions. UA was demonstrated to be active against different tumor cell lines (Chuang et al., 2016, Aguiriano-Moser et al., 2015, Kim and Moon, 2015), its anti-tumoral effect being associated to apoptosis induction by intrinsic and extrinsic pathways of death (Li et al., 2014, Meng et al., 2015, Zhang et al., 2016, Villar et al., 2016). …”

Inhibitory effects of ursolic acid on osteoclastogenesis and titanium particle-induced osteolysis are mediated primarily via suppression of NF-κB signaling

“…Several studies evaluating the pharmacological mechanism of UA action have focused on its anticancer, hepatoprotective, antihyperlipidemic, and anti-depression effects. These studies have revealed that UA modulates signal transducer and activator of transcription 3 (STAT3) [7], mitogen-activated protein kinases (MAPKs) [8], peroxisome proliferator-activated receptors (PPARs) [9], transforming growth factor-b (TGF-b)/Smad signaling [10], and nuclear factor-kB (NF-kB) [11]. However, the effects of UA on bone metabolism remain unclear.…”