Inhibitory effects of terrein on lung cancer cell metastasis and angiogenesis

Abstract

Cancer metastasis is the leading cause of mortality in cancer patients. Over 70% of lung cancer patients are diagnosed at advanced or metastatic stages, and this results in an increased incidence of mortality. Terrein is a secondary bioactive fungal metabolite isolated from Aspergillus terreus . Numerous studies have demonstrated that terrein has anticancer properties, but in the present study, the cellular mechanisms underlying the inhibition of lung cancer cell metastasis by terrein was investigated for the first time. Using MTT assays, the cytotoxic effects of terrein were first examined in human lung cancer cells (A549 cells) and then compared with its cytotoxic effects in three noncancer control cell lines (Vero kidney, L6 skeletal muscle and H9C2 cardiomyoblast cells). The results indicated that terrein significantly reduced the viability of all these cells but exhibited a different level of toxicity in each cell type; these results revealed a specific concentration range in which the effect of terrein was specific to A549 cells. This significant cytotoxic effect of terrein in A549 cells was verified using LDH assays. It was then demonstrated that terrein attenuated the proliferation of A549 cells using IncuCyte image analysis. Regarding its antimetastatic effects, terrein significantly inhibited A549 cell adhesion, migration and invasion. In addition, terrein suppressed the angiogenic processes of A549 cells, including vascular endothelial growth factor (VEGF) secretion, capillary-like tube formation and VEGF/VEGFR2 interaction. These phenomena were accompanied by reduced protein levels of integrins, FAK, and their downstream mediators (e.g., PI3K, AKT, mTORC1 and P70S6K). All these data indicated that terrein was able to inhibit all the major metastatic processes in human lung cancer cells, which is crucial for cancer treatment.

Chemical Constituents of the Deep-Sea-Derived Penicillium citreonigrum MCCC 3A00169 and Their Antiproliferative Effects

“…Compound 7 showed cytotoxicity against several cancer cells, with IC 50 values ranging from 2.6 to 12.9 µM. Terrein ( 14) displayed strong cytotoxicities against human breast cancer MCF-7 cells [38] and human lung cancer A 549 cells [39]. Hence, our findings were consistent with those reported in previous experiments, though different cancer cell lines were evaluated.…”

Novel Angiogenic Regulators and Anti-Angiogenesis Drugs Targeting Angiogenesis Signaling Pathways: Perspectives for Targeting Angiogenesis in Lung Cancer

“…Terrein can simultaneously inhibit VEGF-A/VEGFR-2 and Integrin/focal adhesion kinase (Integrin/FAK) in A549 cells, in addition to reducing protein levels of downstream mediators, such as PI3K, AKT, mTORC1, and P70S6K, and expression of MMP-2 and MMP-9. Mechanically, Terrein inhibits the PI3K/AKT/mTOR signaling pathway by inhibiting HIF-1α and VEGF translation and angiogenesis in lung cancer ( 83 ). Similarly, studies have shown that fibrinogen α (FGA) can inhibit the proliferation, migration and angiogenesis of lung cancer cells by inhibiting the Integrin/AKT/mTOR signaling pathway, promoting cell apoptosis and exerting an anticancer role ( 84 ).…”

Extracellular Regucalcin Suppresses the Growth, Migration, Invasion, and Adhesion of Metastatic Human Prostate Cancer Cells

“…The effect of exogenous regucalcin on cancer cell adhesion was determined using Matrigel [44]. Briefly, 24-well plates were coated with 100 μL Matrigel Matrix (1:1 diluted in sterilized PBS, Corning) and incubated at 37°C for 2 h, and then the extra Matrigel was removed.…”