Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer

Abstract

Although angiogenesis inhibitors targeting VEGF/VEGFR2 have been applied for tumor therapy, the outcomes are still unsatisfactory. Thus, it is urgent to develop novel angiogenesis inhibitor for cancer therapy from new perspectives. Identification of novel angiogenesis inhibitor from natural products is believed to be one of most promising strategy. In this study, we showed that pristimerin, an active agent isolated from traditional Chinese herbal medicine Celastrus aculeatus Merr, was a novel tumor angiogenesis inhibitor that targeting sonic hedgehog (Shh)/glioma associated oncogene 1 (Gli1) signaling pathway in non-small cell lung cancer (NSCLC). We showed that pristimerin affected both the early-and late-stage of angiogenesis, suggesting by that pristimerin inhibited Shh-induced endothelial cells proliferation, migration, invasion as well as pericytes recruitment to the endothelial tubes, which is critical for the new blood vessel maturation. It also suppressed tube formation, vessel sprouts formation and neovascularization in chicken embryo chorioallantoic membrane (CAM). Moreover, it significantly decreased microvessel density (MVD) and pericyte coverage in NCI-H1299 xenografts, resulting in tumor growth inhibition. Further research revealed that pristimerin suppressed tumor angiogenesis by inhibiting the nucleus distribution of Gli1, leading to inactivation of Shh/Gli1 and its downstream signaling pathway. Taken together, our study showed that pristimerin was a promising novel antiangiogenic agent for the NSCLC therapy and targeting Shh/Gli1 signaling pathway was an effective approach to suppress tumor angiogenesis.

CRISPR editing of the GLI1 first intron abrogates GLI1 expression and differentially alters lineage commitment

“…GANT-61, which interferes with GLI1 binding, inhibited mesodermal commit- xenograft models. 54 With regard to osteogenesis, studies in mice demonstrated that GLI1 can induce early osteoblast differentiation during bone formation. 43 Furthermore, GLI1 regulates mature bone metabolism by promoting osteoblast differentiation and repressing osteoblast maturation toward osteocytes.…”

“…GANT‐61, in addition to its apoptotic and antiangiogenic effects, also reduces stem cell markers in cancer cells 53 . Furthermore, SHH/GLI inhibitors other than GANT‐61 also suppress tumor angiogenesis and tumor growth in xenograft models 54 …”

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

“…Pristimerin treatment has been reported to inhibit Shh-induced endothelial cellular essential processes during angiogenesis, with a concomitant abrogation of Shh-induced pericytes recruitment to the new blood vessels which is crucial for the maturation of blood vessels. Besides, Gli1 nucleus distribution in endothelial cells and pericytes was also repressed upon pristimerin treatment (17).…”

“…The first research hotspot is multi-targeted molecular and biological mechanisms associated with pristimerin treatment in cancers. Various targets and pathways are involved in pristimerin treatment, including EGFR/HER2 (38), IGF-1R (23), PI3K/AKT pathway (105), NF-kB pathway (43), ROS generation (28), MAPK pathway (27), EphB4/CDC42/N-WASP pathway (19), Wnt/b-catenin pathway (22), Shh/Gil1 pathway (17), HIF-1a/SPHK-1 pathway (24), Micro RNA (9), proteasome (25), telomerase (26), etc. These molecular events ultimately determine tumor cell fates including cell cycle arrest, apoptosis, autophagy, migration, invasion, metastasis, EMT, CSCs, angiogenesis, etc.…”

“…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).…”