Ursolic Acid, a Pentacyclin Triterpene, Potentiates TRAIL-induced Apoptosis through p53-independent Up-regulation of Death Receptors

Abstract

Discovery of the molecular targets of traditional medicine and its chemical footprints can validate the use of such medicine. In the present report, we investigated the effect of ursolic acid (UA), a pentacyclic triterpenoid found in rosemary and holy basil, on apoptosis induced by TRAIL. We found that UA potentiated TRAIL-induced apoptosis in cancer cells. In addition, UA also sensitized TRAIL-resistant cancer cells to the cytokine. When we investigated the mechanism, we found that UA down-regulated cell survival proteins and induced the cell surface expression of both TRAIL receptors, death receptors 4 and 5 (DR4 and -5). Induction of receptors by UA occurred independently of cell type. Gene silencing of either receptor by small interfering RNA reduced the apoptosis induced by UA and the effect of TRAIL. In addition, UA also decreased the expression of decoy receptor 2 (DcR2) but not DcR1. Induction of DRs was independent of p53 because UA induced DR4 and DR5 in HCT116 p53؊/؊ cells. Induction of DRs, however, was dependent on JNK because UA induced JNK, and its pharmacologic inhibition abolished the induction of the receptors. The down-regulation of survival proteins and up-regulation of the DRs required reactive oxygen species (ROS) because UA induced ROS, and its quenching abolished the effect of the terpene. Also, potentiation of TRAIL-induced apoptosis by UA was significantly reduced by both ROS quenchers and JNK inhibitor. In addition, UA was also found to induce the expression of DRs, down-regulate cell survival proteins, and activate JNK in orthotopically implanted human colorectal cancer in a nude mouse model. Overall, our results showed that UA potentiates TRAIL-induced apoptosis through activation of ROS and JNK-mediated up-regulation of DRs and down-regulation of DcR2 and cell survival proteins.More than 80% of people around the world, for their dayto-day medicinal needs, rely on traditional medicine, which has been around for centuries. Even modern medicine in most instances relies on natural products, and 70% of anticancer drugs have their roots in products derived from nature (1). The search for signature genes of different cancers has shown that most cancers are due to dysregulation of multiple genes and multiple cell signaling pathways; thus, drugs that are multitargeted (once called "dirty drugs") are needed. Compounds from natural sources have an advantage in that they are usually multitargeted. One such compound is ursolic acid (UA), 2 a pentacyclic triterpenoid that has been identified in a large variety of medicinal herbs and other plants, including rosemary (Rosemarinus officinalis), apples (Malus domestica), cranberries (Vaccinium macrocarpon), beefsteak (Perilla frutescens), pears (Pyrus pyrifolia), plum (Prunus domestica), bearberries (Arctostaphylos alpina), loquat (Eriobotrya japonica), scotch heather (Calluna vulgaris), basil (Ocimum sanctum), and jamun (Eugenia jambolana) (2). It has been shown that UA can inhibit cell growth and induce apoptosis in various tumors (3-9). UA induces...

Genotoxicity of polar and apolar extracts obtained from Qualea multiflora and Qualea grandiflora

“…However, Prasad et al (2010) claim that the ursolic acid (a pentacyclic terpene) induced the formation of reactive oxygen species (ROS) and promoted apoptosis in a tumour-derived cell strain. The same effects were observed using other pentacyclic terpenes, such as asiatic acid (Park et al, 2005) and betulinic acid (Wick et al, 1999).…”

Pomolic acid induces apoptosis in SK-OV-3 human ovarian adenocarcinoma cells through the mitochondrial-mediated intrinsic and death receptor-induced extrinsic pathways

“…This indicates that PA induces apoptosis through the death receptor-induced extrinsic pathway. Recently, triterpenoids such as celastrol and ursolic acid have been suggested to potentiate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through upregulation of DR4 and/or DR5 (16,17). In our previous study, 3-O-acetyloleanolic acid was also shown to induce apoptosis in HCT-116 cells, which is mediated by upregulation of DR5 (18).…”

Ursolic acid induces ER stress response to activate ASK1–JNK signaling and induce apoptosis in human bladder cancer T24 cells

“…Recent studies including ours [1] have confirmed the anti-growth ability of ursolic acid against a number of human cancer cells [2][3][4][5]. In addition, ursolic acid has showed a broad spectrum of activities to influence cancer progression and development, including interfering tumorigenesis, metastasis and angiogenesis, and inducing tumor cell apoptosis and differentiation [3][4][5].…”