Anti-Invasion and Antiangiogenic Effects of Stellettin B through Inhibition of the Akt/Girdin Signaling Pathway and VEGF in Glioblastoma Cells

Abstract

Angiogenesis and invasion are highly related with tumor metastatic potential and recurrence prediction in the most aggressive brain cancer, glioblastoma multiforme (GBM). For the first time, this study reveals that marine-sponge-derived stellettin B reduces angiogenesis and invasion. We discovered that stellettin B reduces migration of glioblastoma cells by scratch wound healing assay and invasion via chamber transwell assay. Further, stellettin B downregulates Akt/Mammalian Target of Rapamycin (Akt/mTOR) and Signal transducer and activator of transcription 3 (Stat3) signaling pathways, which are essential for invasion and angiogenesis in glioblastoma. This study further demonstrates that stellettin B affects filamentous actin (F-actin) rearrangement by decreasing the cross-linkage of phosphor-Girdin (p-Girdin), which attenuates glioblastoma cell invasion. Moreover, stellettin B blocks the expression and secretion of a major proangiogenic factor, vascular endothelial growth factor (VEGF), in glioblastoma cells. Stellettin B also reduces angiogenic tubule formation in human umbilical vein endothelial cells (HUVECs). In vivo, we observed that stellettin B decreased blood vesicle formation in developmental zebrafish and suppressed angiogenesis in Matrigel plug transplant assay in mice. Decreased VEGF transcriptional expression was also found in stellettin B–treated zebrafish embryos. Overall, we conclude that stellettin B might be a potential antiangiogenic and anti-invasion agent for future development of therapeutic agents for cancer therapy.

Decreased expression levels of ELOVL6 indicate poor prognosis in hepatocellular carcinoma

“…Chronic hypoxia can result in the disorder of lipid metabolism and an increase in vascular endothelial growth factor expression in hepatocytes, thereby increasing blood flow in the liver to adapt to the anoxic environment. In HCC, the formation of these microvessels also increases the migration ability of tumor cells (47,48). Vascular invasion of tumors is a complex process that utilizes the motility of tumor cells and the proliferation and migration of vascular endothelial cells (49,50).…”

In Vitro and In Vivo Neuroprotective Effects of Stellettin B Through Anti-Apoptosis and the Nrf2/HO-1 Pathway

“…Subsequent studies implicated the PI3K/Akt pathway in the antitumor property of SB and in PD [33,35,36,37,38]. Our recent study demonstrated that SB exhibits anti-invasion and anti-angiogenesis effects likely through the Akt/Girdin pathway in glioblastoma, a common and aggressive malignant primary cancer of the central nervous system [39]. However, the neuroprotective function of SB has not been investigated.…”

Collective Locomotion of Human Cells, Wound Healing and Their Control by Extracts and Isolated Compounds from Marine Invertebrates

“…Molecules 2020, 25, x FOR PEER REVIEW 5 of 42 appeared to be based, at least in part, upon the p-Akt downsignalling-mediated inhibition of the interaction between F-actin and the actin-binding protein P-girdin, responsible for pseudopoda extension at the cell leading edge, and the expression of matrix metalloprotease 2, phosphorylated integrin β1 and phosphorylated focal adhesion kinase by this cancer cytotype [43]. In consideration that glioblastoma cell survival and the angiogenetic processes in models in vitro and in vivo are also remarkably reduced in the presence of stellettin B [42], this molecule is a strong candidate as anti-cancer agent against malignant brain tumors. Negombata magnifica (Keller, 1889; Demospongiae, Poecilosclerida: Podospongiidae), formerly named Latrunculia magnifica, is also known as toxic finger-sponge and it typically has a brilliant orange-red coloration and a digitate or leafy morphology with crooked branches ( Figure 4A).…”

“…A number of anti-cancer bioactive molecules have been isolated from this marine invertebrate, such as jaspiferins, jaspiferals, stelliferins, and stellettin [34][35][36][37][38][39][40][41]. In their publication, Cheng et al [42] produced additional data regarding the mobility control exercised by the triterpenoid stellettin B (3Z,3aS,5aR,9aR,9bS)-3a,6,6,9a-tetramethyl-3-[(3E,5E)-6-(5-methyl-6-oxopyran-2-yl)hepta-3,5-dien-2-ylidene]-4,5,5a,8,9,9bhexahydro-1Hcyclopenta [a]naphthalene-2,7-dione; Figure 3B on human U87MG and GBM8401 glioblastoma cells. In particular, the migration and invasion of tumor cells was inhibited in both scratch wound healing and transwell chamber assays when exposed to an increasing concentration of the triterpene in the range between 1 and 10 µM.…”