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

• Published in: Cancers Vol. 11; no. 2; p. 220
• Main Authors: Cheng, Shu-Yu, Chen, Nan-Fu, Lin, Pi-Yu, Su, Jui-Hsin, Chen, Bing-Hung, Kuo, Hsiao-Mei, Sung, Chun-Sung, Sung, Ping-Jyun, Wen, Zhi-Hong, Chen, Wu-Fu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.02.2019; MDPI
• Subjects: Actin; AKT protein; Angiogenesis; Apoptosis; Brain cancer; Cancer therapies; Cell adhesion & migration; Cell growth; Cell migration; Cross-linkage; Cytoskeleton; Danio rerio; Embryos; Endothelial cells; Girdin; Glioblastoma; Glioblastoma cells; Glioblastoma multiforme; glioblastoma multiforme (GBM); Hypoxia; invasion; Kinases; Lung cancer; Medical prognosis; Metastases; Metastasis; Phosphorylation; Proteins; Rapamycin; Signal transduction; Stat3 protein; stellettin B; TOR protein; Transcription; Tumorigenesis; Tumors; Umbilical vein; Vascular endothelial growth factor; VEGF; Wound healing; glioblastoma multiforme (GBM); stellettin B; invasion; Girdin; VEGF; angiogenesis
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers11020220

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.