Pristimerin attenuates cell proliferation of uveal melanoma cells by inhibiting insulin‐like growth factor‐1 receptor and its downstream pathways

Abstract

Uveal melanoma (UM) has a high mortality rate due to liver metastasis. The insulin‐like growth factor‐1 receptor (IGF‐1R) is highly expressed in UM and has been shown to be associated with hepatic metastases. Targeting IGF signalling may be considered as a promising approach to inhibit the process of metastatic UM cells. Pristimerin (PRI) has been demonstrated to inhibit the growth of several cancer cells, but its role and underlying mechanisms in the IGF‐1‐induced UM cell proliferation are largely unknown. The present study examined the anti‐proliferative effect of PRI on UM cells and its possible role in IGF‐1R signalling transduction. MTT and clonogenic assays were used to determine the role of PRI in the proliferation of UM cells. Flow cytometry was performed to detect the effect of PRI on the cell cycle distribution of UM cells. Western blotting was carried out to assess the effects of PRI and IGF‐1 on the IGF‐1R phosphorylation and its downstream targets. The results indicated that IGF‐1 promoted the UM cell proliferation and improved the level of IGF‐1R phosphorylation, whereas PRI attenuated the effect of IGF‐1. Interestingly, PRI could not only induce the G1 phase accumulation and reduce the G2 phase induced by IGF‐1, but also could stimulate the expression of p21 and inhibit the expression of cyclin D1. Besides, PRI could attenuate the phosphorylations of Akt, mTOR and ERK1/2 induced by IGF‐1. Furthermore, the molecular docking study also demonstrated that PRI had potential inhibitory effects on IGF‐1R. Taken together, these results indicated that PRI could inhibit the proliferation of UM cells through down‐regulation of phosphorylated IGF‐1R and its downstream signalling.

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

“…This confirms previous observations in primary UM cell lines and UM samples [ 108 , 109 , 110 , 111 ] as well as in mUM [ 112 ]. Insulin-like growth factor-1 is a strong mitogen, which on stimulating IGF-1R signalling plays an important role in UM development and spread [ 113 ]. Hence, targeting IGF signalling has been considered a promising approach to inhibit the process of metastatic UM cells, e.g., recent studies have looked at this pathway using single [ 113 ] and a combinatory targeted approach [ 114 ].…”

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

“…Xie et al have suggested that pristimerin inhibits IGF-1R/Akt/mTOR and ERK1/2 pathways and consequently leads to the loss of UM cell viability. They have also found that IGF-1 stimulates the expression of cyclin D1, which can be reversed by pristimerin to induce G1 phase arrest (23).…”

“…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).…”

“…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).…”

Pristimerin Suppresses RANKL-Induced Osteoclastogenesis and Ameliorates Ovariectomy-Induced Bone Loss

“…Pristimerin, a natural triterpenoid compound, isolated from the traditional Chinese herbs Celastraceae and Hippocrateaceae , has shown numerous biological and pharmacological properties, such as anti-inflammatory ( Yadav et al, 2010 ), anti-oxidative ( Dos Santos et al, 2010 ; Hui et al, 2014 ), anti-tumor ( Li et al, 2019 ), anti-malarial ( Figueiredo et al, 1998 ) and anti-fungal effects ( Luo et al, 2005 ; Gullo et al, 2012 ). Many previous studies have confirmed that Pristimerin exerts its pharmacological effects through inactivating NF-κB and MAPK signaling ( Deeb et al, 2014 ; Yousef et al, 2018 ; Xie et al, 2019 ), which are similar pathways involved in osteoclastogenesis. However, the role of Pristimerin on osteoclastogenesis need further investigation.…”