Role of AMPK and PPARα in the anti‐skin cancer effects of ursolic acid

Abstract

The phytonutrient ursolic acid (UA), present in apples, rosemary, and other plant sources, has anti-cancer properties in a number of systems, including skin cancers. However, few reports have examined upstream mechanisms by which UA may prevent or treat cancer. Recent reports have indicated UA induces death of cancer cell lines via AMP-activated protein kinase (AMPK), an energy-sensing kinase which possesses both pro-metabolic and anti-cancer effects. Other studies have shown UA activates peroxisome proliferator activated receptor α (PPARα) and the glucocorticoid receptor (GR). Here, we found the cytotoxic effect of UA in skin carcinoma cells required AMPK activation. In addition, two inhibitors of PPARα partially reversed the cytotoxic effects of UA, suggesting its effects are at least partially mediated through this receptor. Finally, inhibition of the GR did not reverse the effects of UA nor did this compound bind the GR under the conditions of experiments performed. Overall, studies elucidating the anti-cancer effects of UA may allow for the development of more potent analogues utilizing similar mechanisms. These studies may also reveal the mediators of any possible side effects or resistance mechanisms to UA therapy.

The Bioactivities of Resveratrol and Its Naturally Occurring Derivatives on Skin

“…Resveratrol can also be used as an enhancer to synergize anti-SCC activity of ursolic acid [ 69 ]. Ursolic acid is approved as an efficient natural compound to induce death of skin cancer cell lines via AMP-activated protein kinase [ 70 ]. Resveratrol if used at a concentration of 25 μM enhances antiproliferative effects of ursolic acid in the Ca3/7 cell lines in a dose-dependent fashion.…”

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part I)

“…PPARα has the ability to bind to DNA with Retinoid X Receptor (RXR) as a heterodimer that recognizes specific genes; this process is promoted by agonist ligands, which regulate the gene expression of other transmission factors through protein interactions. The activation of PPARα by UA, however not through direct binding, led to the apoptosis of skin cancer cells that were previously treated with PPARα and AMPK inhibitors [ 231 ]. Within the field of skin cancer, the genomic and epigenomic mechanisms responsible for UA activity on UVB-induced non-melanoma skin cancers were investigated through Cp-methyl sequencing and RNA sequencing; it was reported that UA regulates the IL-6, NF-kB, and Nrf2 inflammatory pathways as well as cell cycle regulatory pathways [ 232 ].…”

Impact of Phytochemicals on PPAR Receptors: Implications for Disease Treatments

“…In addition, UA functioned as a PPAR α agonist to regulate metabolic syndrome, liver diseases, respiratory dysfunction, and exaggerated inflammatory response in the animal and cell line experiments [ 158 , 160 , 162 – 164 ]. Likewise, UA improved cerebral ischemia/reperfusion injury, central nervous system (CNS) neural dysfunction, remyelination, multiple sclerosis (brain/central nervous system irregularities), and also airway inflammation of allergic asthma via promotion of PPAR γ signaling by its PPAR γ agonist potential in in vivo studies [ 159 , 165 , 166 ]. A recent study showed that UA (0-50 μ M) may exert antiskin cancer effects by promoting AMPK and PPAR α in Ca3/7 and MT1/2 premalignant and malignant skin cancer cell lines [ 166 ].…”