Pristimerin‐induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway

Abstract

Uveal melanoma (UM) is a highly invasive intraocular malignancy with high mortality. Presently, there is no FDA‐approved standard for the treatment of metastatic UM. Pristimerin is a natural quinine methide triterpenoid compound with anti‐angiogenic, anti‐cancer and anti‐inflammatory activities. However, Pristimerin potential cytotoxic effect on UM was poorly investigated. In the present study, we found the migration and invasion of UM‐1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death. Pristimerin inhibited Akt and FoxO3a phosphorylation and induced nuclear accumulation of FoxO3a in UM‐1 cells, increased the expression of pro‐apoptotic proteins Bim、p27Kip1, cleaved caspase‐3, PARP and Bax, and decreased the expression of Cyclin D1 and Bcl‐2. LY294002 or Akt‐siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin‐induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM‐1 cell cultures. Taken together, present results showed that Pristimerin induced apoptotic cell death through inhibition of PI3K/Akt/FoxO3a pathway in UM‐1 cells. These findings indicate that Pristimerin may be considered as a potential chemotherapeutic agent for patients with UM.

Alternative Options for Skin Cancer Therapy via Regulation of AKT and Related Signaling Pathways

“…The viability of human uveal melanoma UM-1 cells was inhibited by treatment with pristimerin, a quinine methide triterpenoid compound derived from Celastraceae and Hippocrateaceae and the apoptosis induction was mediated by disrupting the mitochondrial membrane potential and increasing the ROS production. Furthermore, pristimerin reduced migration and invasion by the regulation of pAKT and pFoxO3a expression with confirming the knock-down of AKT in UM-1 cells [ 61 ]. In human A375 and mouse B16F10 melanoma cells, bioactive compounds such as gambogic acid [ 62 ], melittin [ 63 ], kaempferol [ 64 ], euplotin C [ 65 ], lycorine [ 66 ], oxyfadichalcone C [ 67 ], isoliquiritigenin [ 68 ], muniziqi granule/harmine [ 69 ], apigenin [ 70 ] and casticin [ 71 ] inhibited cell proliferation, colony formation, migration and invasion by downregulating the expression of pPI3K, pAKT, pmTOR and pGSK3 β together with the expression of related biomarkers including p27, cyclin D1, LC3, 4EBP1, Bax, Bcl-2 and MMPs.…”

Cellular and Molecular Mechanisms of Pristimerin in Cancer Therapy: Recent Advances

“…Emerging evidence has shown that pristimerin treatment gives rise to cell accumulation in G0/G1 phases and cell reduction in S and G2/M phases, indicating the induction of G0/G1 phase arrest to exhibit anti-proliferative effects on various cancers including CRC (22,38), breast cancer (9,21), uveal melanoma (UM) (18,23,30), chronic myelogenous leukemia (CML) (39), oral squamous cell carcinoma (OSCC) (27), esophageal cancer (40), pancreatic cancer (26,41), prostate cancer (24,25) and cholangiocarcinoma (42). However, a study related to the imatinib-resistant CML has found that pristimerin does not significantly affect the cell cycle other than the emergence of cells in the sub-G1 apoptotic phase (43).…”

“…Considerable evidence has revealed that under pristimerin treatment, morphological changes associated with apoptosis occur in UM (18), breast cancer (21,49,50), CML (39), hepatocellular carcinoma (HCC) (51), and glioma (52). Pristimerin has been reported to induce chromatin condensation and nuclei fragmentation accompanied by cell shrinkage.…”

“…The intrinsic mitochondrial pathway is initiated within the cell. There are various internal stimulating factors inducing apoptosis such as ROS (18,39,51,52,(54)(55)(56), and hypoxia (31). Pristimerin could promote ROS generation and lead to the loss of mitochondrial membrane potential, suggesting the occurrence of mitochondrial dysfunction (9,30,38,50,(55)(56)(57).…”

“…It has been reported that pristimerin exhibits many biological effects, such as insecticidal (11), antiinflammatory (12), anti-angiogenic (13), anti-bacterial (14), antiviral (15), anti-fungal (16) and anti-tumor effects (9). Pristimerin exhibits pharmacological effects against tumors through different targets and signal transduction pathways, including sonic hedgehog (Shh)/glioma-associated oncogene homolog 1 (Gli1) (17), phosphatidylinositol 3-kinase (PI3K)/Akt (18), erythropoietin-producing hepatoma receptor B4 (EphB4)/ CDC42/neural Wiskott-Aldrich syndrome protein (N-WASP) (19), nuclear factor-kappaB (NF-kB) (20), reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK) (21), Wnt/b-catenin (22), insulin-like growth factor type 1 receptor (IGF-1R) (23), and hypoxia inducible factor 1a (HIF-1a)/ sphingosine kinase 1 (SPHK1) (24)pathways as well as micro RNA (9), proteasome (25) and telomerase (26). Pristimerin suppresses cancer cell proliferation via G1 phase arrest (27), apoptosis (28) and autophagy induction (21).…”